Interplay between group A Streptococcus and host innate immune responses

Marcia Shu-Wei Su; Yi-Lin Cheng; Yee-Shin Lin; Jiunn-Jong Wu

doi:10.1128/mmbr.00052-22

. 2024 Mar 7;88(1):e00052-22. doi: 10.1128/mmbr.00052-22

Interplay between group A Streptococcus and host innate immune responses

Marcia Shu-Wei Su ^1,^2,^#, Yi-Lin Cheng ^3,^4,^5,^6,^#, Yee-Shin Lin ^5,^6,^✉, Jiunn-Jong Wu ^1,^2,^7,^✉

Editor: Corrella S Detweiler⁸

PMCID: PMC10966951 PMID: 38451081

SUMMARY

Group A Streptococcus (GAS), also known as Streptococcus pyogenes, is a clinically well-adapted human pathogen that harbors rich virulence determinants contributing to a broad spectrum of diseases. GAS is capable of invading epithelial, endothelial, and professional phagocytic cells while evading host innate immune responses, including phagocytosis, selective autophagy, light chain 3-associated phagocytosis, and inflammation. However, without a more complete understanding of the different ways invasive GAS infections develop, it is difficult to appreciate how GAS survives and multiplies in host cells that have interactive immune networks. This review article attempts to provide an overview of the behaviors and mechanisms that allow pathogenic GAS to invade cells, along with the strategies that host cells practice to constrain GAS infection. We highlight the counteractions taken by GAS to apply virulence factors such as streptolysin O, nicotinamide-adenine dinucleotidase, and streptococcal pyrogenic exotoxin B as a hindrance to host innate immune responses.

KEYWORDS: group A Streptococcus, innate immunity, complement system, phagocytosis, autophagy, LC3-associated phagocytosis, inflammation, pyroptosis

INTRODUCTION

Group A Streptococcus (GAS), also termed Streptococcus pyogenes, is a human-specific Gram-positive catalase (CAT)-negative pathogen with characteristic β-hemolysis. It has more than 200 reported emm serotypes. GAS infections encompass a broad spectrum of diseases from mild infections to severe invasive group A Streptococcus (iGAS) illnesses. Globally, GAS is estimated to cause 1.78 million new cases and 517,000 deaths annually in low- and middle-income countries (1). GAS often infects the skin or throats of humans, especially children younger than 15 years old. Common cases of mild GAS infections are diagnosed as pharyngitis, scarlet fever, and impetigo. GAS infections usually can be easily treated with the administration of penicillin and other clinical antibiotics (cephalosporins, macrolides, and clindamycin). However, if not treated properly, infections can cause life-threatening iGAS-induced bacteremia, puerperal sepsis, cellulitis, necrotizing fasciitis, and streptococcal toxic shock syndrome. After repeated GAS infection occurs, hosts’ immune systems may react against their own tissues causing autoimmune diseases. For instance, rheumatic fever causes inflammation and scarring of heart valves that lead to a progressive rheumatic heart disease (RHD) (1 –3). The World Health Assembly has consequently called for increased global awareness of GAS-triggered RHD in 2018. An increase in cases of iGAS disease and scarlet fever in the European region, defined by the World Health Organization (WHO) (https://www.who.int/europe/home?v=welcome), was reported during the COVID-19 pandemic in 2022. Therefore, the development of licensed GAS vaccines is crucial. This was one of the high-priority recommendations made by the WHO’s Strategic Advisory Group of Experts on Immunization in 2023. However, owing to serotype diversity, antigenic variation, and the potential for autoimmune sequelae that GAS causes, the development of GAS vaccines has for decades been a challenge for researchers.

To develop new strategies for the prevention of GAS infection, it is vital to understand host immune responses to the infection of this bacterium. The infectious events of GAS comprise several steps (Fig. 1, left panel). First, human skin and mucosae (physical barriers in the epidermis) are the first line of defense against GAS attachment. They form a barrier immune system that is recognized as a part of the innate immune system. Next, besides the physical barriers that prevent the entry of pathogens, chemical barriers in the dermis also enhance the effectiveness of this barrier immune system. For example, complement-mediated opsonization and anti-microbial peptides (defensins) that are secreted from mucosal epithelial tissue assist in preventing GAS invasions. The barrier immune system, however, is not perfect. When it gets breached, GAS can defend against host cellular immune attacks and may aggressively infect host cells in the dermis, ultimately resulting in GAS dissemination in deeper tissues and the development of a range of diseases with varying levels of severity. To better control the damage that GAS infections may cause, host cells initiate a multitude of innate immune responses (4). In the past, GAS was recognized as an extracellular bacterium. However, a growing body of evidence has demonstrated that GAS can also invade human cells. This GAS internalization is an immune escape mechanism that helps iGAS evade antibiotics and phagocytosis. This evasion has been shown by the increase in antibiotic treatment failures, which may be due in part to an increase in iGAS and the protective intracellular niches (5).

Fig 1 — Overview of GAS evasion strategies against host innate immune responses. To achieve a successful infection and invasion, GAS needs to defend against several mechanisms of host innate immune responses. The infectious events of GAS comprise several steps: GAS overcomes physical barriers in the epidermis, combats chemical barriers and host immune attacks in the dermis, and disseminates in deeper tissues. (A) To establish an initial attachment with the extracellular matrices (ECMs) of human skin and mucosae, encapsulated GAS builds a firm adhesion to the ECMs by interacting GAS adhesins (M protein, protein F1, and *S. pyogenes* fibronectin-binding protein) with host cellular surface receptors (fibronectin, laminin, and collagen). (B) When there are breached skin/mucosae, GAS or complement-opsonized GAS enters and aggressively infects host cells. The opsonization of GAS includes C1 recognizing mannose-IgG interactions, as well as mannose-binding lectin (MBL) associated with the mannan-binding lectin serine protease family (MASP). GAS possesses various virulence factors [M protein, complement evasion factor (CEF), streptococcal pyrogenic exotoxin B (SpeB), streptococcal C5a peptidase, and more] affecting complement functions. (C) The internalization of GAS is the first step of phagocytosis. The types of cellular receptors include the Fc gamma receptors (Fc_γRs), lectin receptors (LRs), complement receptors (CRs), and toll-like receptors (TLRs). Once GAS is engulfed inside a phagosome, host cells generate NADPH oxidase-2 (NOX2)-mediated reactive oxygen species (ROS), cationic anti-microbial peptides (AMPs), neutrophil extracellular traps (NETs), and fusion with lysosomes to eliminate invading GAS. By contrast, GAS expresses streptolysin O (SLO), nicotinamide-adenine dinucleotidase (NADase), deoxyribonucleases (DNases), streptodornase (Sda), and streptococcal collagen-like protein (SclA) to counteract phagocytosis for survival. (D) Host selective autophagy (xenophagy) has been reportedly activated by GAS infection in human epithelial cells. The intracellular GAS can be restrained in endosomes and eliminated by endosome-lysosome fusion. However, some GAS strains express pore-forming cytotoxin SLO to disrupt the endosome and to free themselves into the cytoplasm. GAS NADase is co-expressed with SLO and secreted to the cytoplasm through the SLO-forming pores. This process recruits host light chain 3 (LC3) and specific autophagy machinery for canonical autophagy, such as autophagy-related gene 14 (ATG14)- and AMBRA1-containing phosphotidylinositol 3-kinase (PI3K) complex with core components beclin1, VPS15, and VPS34. The LC3 and autophagy machinery are recruited to the escaping GAS, where it begins to form a double-membrane phagophore-like structure. The escaping GAS is ultimately enclosed into double-membrane autophagosomes, which are also known as GAS containing LC3-positive autophagosome-like vacuoles (GcAVs). By fusion with lysosomes, the GAS of the GcAVs would either be killed by xenophagy or survive by insufficient acidification caused by GAS SLO and NADase. (E) Differing from phagocytosis and xenophagy, host cells also employ LC3-associated phagocytosis (LAP) to combat GAS invasion. LAP is activated by Fc_γR or CR-mediated internalization, followed by the assembly of a unique Rubicon- and UVRAG-containing PI3K Class III sub-complex and NOX2-derived ROS production. ROS and phosphatidylinositol 3-phosphate (PI3P) promote LC3 lipidation and the recruitment of downstream ATG conjugation systems to form GAS containing LC3-positive LAP-engaged phagosomes [LC3-associated phagosomes (LAPosomes)]. In human endothelial cells, the acidity of the single-membrane GAS containing LAPosomes is not adequate because of GAS SLO and NADase, leading to GAS multiplication in endothelial cells. (F) GAS-induced inflammation is a host-protective mechanism by recruitment of immune cells to counteract GAS attachment, multiplication, and dissemination. When host cells sense GAS, they activate the expression of the pattern recognition receptors [i.e., LR, nucleotide-binding and oligomerization domain-like receptors (NLRs)] and toll-like receptor 2 on cell surfaces for inflammasome activation. Once GAS is internalized in endosomes, the endosome-bound TLR8 and TLR9 detect GAS nucleic acids, debris, or soluble M proteins. This recognition enhances the expression of host transcription factors including nuclear factor kappa B (NF-κB). The transcriptional NF-κB further triggers the expression of pro-inflammatory genes such as tumor necrosis factor (TNF), interleukin (IL)-6, and pro-IL-1β, which mediate the recruitment and activation of macrophages and neutrophils. GAS M1 proteins also serve as the second signal to induce the activation of the NLR family pyrin domain-containing 3 (NLRP3)-mediated inflammasome. Accompanying M proteins, GAS pore-forming streptolysin S (SLS) and SLO activate the inflammasome pathway to induce the production of IL-1β and cell death. (G) Cell death can be triggered by varying GAS virulence factors. GAS soluble M proteins reportedly activate IL-1β signaling in the early phase of infection. Besides M proteins, GAS secretes SLS and SLO to form pores on cell membrane and induces cell death resulting from K⁺ efflux. GAS SpeB cleaves pro-IL-1β to IL-1β in an inflammasome-independent manner. The mature IL-1β will couple with NLRP3 inflammasome that promote pyroptotic cell death by exporting IL-1β through gasdermin D (GSDMD) pores. In keratinocytes, GAS SpeB cleaves gasdermin A (GSDMA) into the carboxyl-terminal domain of GSDMA (C-GSDMA) and amino-terminal domain of GSDMA (N-GSDMA). The multiple N-GSDMAs form pores on cell membrane, leading to GSDMA-dependent pyroptosis that restricts local inflammation and eliminates GAS.

There has been a large amount of research undertaken in recent years on GAS-related pathogenesis, invasion, evasion, and interactions with host cells. The comprehensive GAS pathogenesis studies investigate necrotizing myositis in non-human primates and intact skin infection in a murine model using short-read dual RNA sequencing approaches (6, 7). Their findings related to host responses to GAS infection mimic human responses. However, some results may not be generalizable to humans. This issue might be resolved by the use of advanced three-dimensional (3D) human organoids (i.e., skin or skeleton muscle models). Another noteworthy fact is that those studies appear to lack differential expression profiles of host RNA isoforms that reflect the different progressions of GAS infection using short-read RNA sequencing. Nonetheless, the majority of the studies on GAS-host interaction are narrowly focused on one or two mechanisms. Therefore, without a comprehensive understanding of the different ways iGAS infections develop and the corresponding cellular events, it is difficult to appreciate the many interrelated strategies that GAS employs to overcome the interactive immune responses of host cells.

This review article attempts to provide an overview of the behaviors and mechanisms that allow GAS to infect epithelial, endothelial, and professional phagocytic cells and to survive innate immune responses based on the body of research on GAS that has been accumulated over the past 20 years. We focus on describing GAS interference with the complement system, GAS attachment and internalization, and GAS-triggered host innate immune responses. With regard to host innate immune responses, because there have been several breakthrough discoveries in recent years, this article discusses GAS interaction with host phagocytosis, selective autophagy, light chain 3 (LC3)-associated phagocytosis (LAP), inflammation, and pyroptosis during infection in detail (Fig. 1). We hope this discussion will provide an up-to-date comprehensive overview of the new research on GAS pathogenesis and GAS-induced innate immune responses, and this overview will aid in the development of iGAS treatment and new strategies to prevent severe iGAS infections.

ARMS RACE BETWEEN THE HOST COMPLEMENT SYSTEM AND GAS VIRULENCE FACTORS

The complement system is composed of numerous circulating proteins found in the bloodstream. Those circulating proteins are called complement molecules, and they act as the chemical barriers of the innate immune system. Once the complement system is activated, it triggers a series of cellular responses in parallel with one another to kill foreign pathogens. These responses include opsonophagocytosis, inflammation, pro-inflammatory chemokine secretion, and cytokine production. The main tasks of the human complement system include pathogen recognition, initiation of phagocytosis and inflammation, attacks on bacterial membrane, and regulation of T- and B-cell responses (Fig. 2) (8 –10). Three distinct pathways (the classical, lectin, and alternative pathways) of the complement system are activated to fight bacterial infections (Fig. 2A) (11). Of those complement factors, the C3 and C5 proteins are the core of this sophisticated system. The conventional roles and newly discovered functions of complement proteins, along with the strategies that GAS employs to evade the complement system and opsonophagocytosis, are briefly described below.

Interfering with the recognition of GAS

Once immunoglobulin (Ig) G binds to GAS, complement molecules recognize it and are attracted (Fig. 2A). Targeting the IgG-complement (C1q) binding is one of the evasion strategies of GAS. The binding of GAS protein H (M protein family) to IgG (Fc region) is facilitated by the GAS M1 protein (12). Moreover, GAS endopeptidase O (PepO) competitively binds to an initiator of the classical pathway C1q with a higher affinity than the IgG binding (13). Using proteolysis approaches, GAS cysteine protease streptococcal pyrogenic exotoxin B (SpeB) and the membrane-activated complex 1/IgG-degrading enzyme of S. pyogenes (Mac-1/IdeS) cleave antibodies to avoid antibody-mediated opsonophagocytosis (14 –16). The N-linked glycan of the IgG heavy chain is cleaved by endoglycosidase (EndoS) secreted by GAS. This cleaving disrupts the interaction between IgG and Fc receptors (17).

Preventing the formation of C3 convertase and degrading C3b opsonin

As shown in Fig. 2, a novel GAS complement evasion factor (CEF) impairs C3 convertase formation by binding to complement C1s through glycan-dependent interactions (18). GAS SpeB not only degrades the C3b opsonin but also the C3 molecule through a C3-binding motif identified in the C-terminal domain of SpeB (Fig. 2C) (19 –21).

Avoiding C3b opsonization and preventing C5 convertase formation

GAS avoids C3b opsonization and deposition (Fig. 2C) through an initial M protein-host fibrinogen binding, which is cleaved by host plasmin (hPm) to generate accumulated fibrin (22). The GAS M-related protein (Mrp) was found to have two fibrinogen-binding sites, according to a study conducted by Courtney and colleagues (23). The Mrp-fibrinogen binding interferes with C3b deposition and opsonophagocytosis via the classical pathway. Besides this process, GAS CEF inhibits C3b deposition on the bacterial surface (18). To prevent C5 convertase formation, CEF binds to C1s, C3, and C5 via glycan-dependent interactions. Last but not least, GAS multifunctional C5a peptidase (ScpA) (Fig. 2B) cleaves C3 to form atypically large fragments of C3a and C3b, reducing the moiety of C3b depositing on the bacterial surface (24).

Degrading C3a and C5a and abolishing recruitment of neutrophils

Chemoattractants C3a and C5a recruit polymorphonuclear neutrophils to the sites of infection. This recruitment signaling is abolished when GAS SpeB and ScpA degrade C3a and C5a (Fig. 2D) (19, 25). The soluble form of GAS Plr/SDH/GAPDH inhibits C5a-mediated chemotaxis by binding to C5a, which allows GAS ScpA to cleave C5a and to reduce its chemotactic signaling (26, 27). A study conducted by Lynskey and colleagues discovered that ScpA is also capable of C3a cleavage, interrupting neutrophil activation, phagocytosis, and chemotaxis (24).

Resisting MAC formation and MAC-induced lysis

Due to the thickness of the GAS cell wall, it is presumed that the membrane attack complex (MAC) is probably not able to penetrate the thick peptidoglycan layer of GAS and cause bacterial death (28). Instead, the CEF inhibits the formation of MAC on the surface of GAS (Fig. 2E) (18). The streptococcal inhibitor of complement (SIC) has been reported to interact with two human plasma proteins, clusterin and histidine-rich glycoprotein, as MAC complex regulators. These interactions block the binding of the C5bC6C7 complex to the GAS membrane. Consequently, the interactions prevent bacterial lysis from making attacks on bacterial membrane by the MAC complex (29, 30).

Tampering with human complement regulators

One of strategies that GAS uses is the hijacking of host proteins to impede complement responses. On the C3b-bound GAS surface, GAS degrades opsonin C3b to an inactive C3b (iC3b) (Fig. 2C) via human factor I (hFI), human factor H (hFH), and human plasminogen (hPg)-derived hPm, hindering the C3 amplification loop of the complement cascade (31). In different emm-type GAS strains, GAS uses a variety of mechanisms to degrade C3b and to evade neutrophil-mediated phagocytosis (Fig. 2C). The GAS FH receptor (FHR) acts to bind hFH to the bacterial surface. As well, the GAS plasminogen-binding group A streptococcal M-like protein (PAM) connects directly to hPg/hPm. In GAS strains that have strong PAM-binding abilities, C3b is cleaved by the hFI-hFH complex and hPm. In these cases, the hFI-hFH complex will then cleave iC3b, while hPm digests and generates small peptides of iC3b (31). In contrast, in GAS strains that have weak hFH-binding abilities, hPg/hPm is indirectly recruited to the bacterial surface via fibrinogen-M protein binding. C3b is cleaved into iC3b by the hFI-hFH complex, though a trace amount of degraded iC3b is found on fibrinogen-bound hPm. Nevertheless, all GAS strains resist phagocytosis in a similar manner regardless of their PAM or hFH-binding affinities (31).

GAS has evolved to manipulate the modulation of host complement activation via two of the major inhibitors, hFH and the human C4-binding protein (hC4BP). The former is involved in the alternative pathway, while the latter is responsive for the classical and lectin pathways. Through hFH-hC4BP interaction, the activity of the C4b (soluble and cell-bound forms) is suppressed, reducing the formation of C3 convertase (C4bC2a complex) and enhancing the decomposition of C3 convertase (32, 33). When hFH and hC4BP are acquired and interact with the GAS surface-bound protein H (M protein family), this GAS protein H aids in the evasion of immune recognition and the complement system (34). Moreover, the binding of human IgG to GAS protein H strengthens the formation of a tripartite complex protein H-IgG-hC4BP (35, 36). GAS streptokinase (Ska) (Fig. 2C) has also been reported to acquire and convert hPg to hPm on the bacterial surface, increasing C3b degradation (37).

GAS ATTACHMENT, INTERNALIZATION, AND GAS-MEDIATED SIGNALING EVENTS

GAS is commonly found in human skin and the mucosal surfaces of the oropharyngeal cavity. In order for GAS to survive in these tissues, it is essential for GAS to adhere and penetrate the mucin layer. This penetration causes the progressive infection and invasion of host cells. Furthermore, researchers have discovered that GAS has come to possess multiple adhesins (Table 1). By working together with different tissue surface receptors (fibronectin, laminin, and basement membrane type IV collagen), GAS is able to implement adhesion, aggregation, colonization, and invasion (38). This bacteria-extracellular matrix (ECM) interaction sequentially transmits “danger signals” from the ECM molecules to the connecting heterodimeric integrins, which mediate the cellular signaling cascade of innate immune responses. The responses include phagocytosis, autophagy, and LC3-associated phagocytosis (39, 40).

TABLE 1.

GAS factors that are involved in adhesion and invasion^a

Host interaction	GAS molecule	Characteristics	Reference
FIRST STEP OF ADHESION: non-specific binding, relatively weak and reversible
GAS molecules approaching host cell surface	LTA	Overcomes electrostatic repulsion by hydrophobic components	(41 –43)
SECOND STEP OF ADHESION: specific covalent bond binding, strong and irreversible
GAS molecules binding to host mucin	M proteins	Invasin. Binds the N-terminal portion of the M protein to host mucin	(41, 44)
GAS molecules binding to host cell surface	HA capsule, which is encoded by has operon	Forms the outer layer of cell wall; helps to resist complement-mediated phagocytosis; assists in M protein-mediated adherence; and binds to CD44 receptor in human keratinocytes	(45 –49)
	LTA	Facilitates in GAS adherence by interacting with fibronectin	(50, 51)
	M6 protein	Binds human membrane cofactor protein (or CD46) in keratinocytes	(52, 53)
	Pili/fimbriae: the genes of pili are encoded in the FCT loci (the fibronectin-binding, collagen-binding, and T antigen loci)	Biofilm formation and colonization	(54, 55)
	Pilus adhesin tip protein	Anti-phagocytic effect that is attributable to pili	(56)
	Pullulanase	GAS adhesin; also possesses glycoprotein-binding and carbohydrate-degrading activities	(57)
GAS proteins binding to host ECM fibronectin (links to integrin α5β1)	FbaA	GAS tissue tropism and fitness; GAS invasion; only found in GAS M1, M2, M4, M22, M28, and M49 strains	(56, 58)
	FbaB and PrtF2/PFBP	GAS adhesion and invasion; involvement of FbaB with severe invasive infections in highly virulent GAS M3 and M18 strains	(59 –63)
	Fbp54	Anchorless adhesin; presence in many serotypes of GAS	(64, 65)
	M1 and M6 proteins	GAS adhesion and invasion; binds host fibronectin in epithelial cells	(66)
	PrtH	M protein-mediated adherence	(67, 68)
	Plr/SDH/GAPDH	Anchorless adhesin; a multifunctional protein binds host fibronectin but not GAS M protein	(69, 70)
	SclA/Scl1	Binds fibronectin and laminin; this ligand-switching mechanism between blood and tissue may augment GAS colonization and dissemination	(71)
	SfbI and its allelic variant PrtF1	Invasin; GAS adhesion and invasion; widely distributes among emm types; binds directly to fibronectin in a co-operative way in epithelial and endothelial cells	(72 –74)
	SfbII	Membrane-anchored fibronectin-binding surface protein in group A streptococci	(75)
	SfbX	Fibronectin-binding proteins that are co-transcribed from the same bi-cistronic mRNA	(76)
	SOF	Virulence factor; fibronectin-binding protein contributes to the pathogenesis of GAS infections in vivo	(77 –79)
GAS proteins binding to host ECM collagen (links to integrin α2β1 and α11β1)	Cpa	Binds specifically to tissues containing type I collagen, enhancing GAS M49 adherence and internalization	(80, 81)
	SclA/Scl1	Universal adhesin; contains a long region of Gly-X-X motifs to form a collagen-like triple-helical structure; regulated by mga; Scl1 binds to cellular integrins α2β1 and α11β1	(82 –84)
	SclB/Scl2	Universal adhesin; contains a long region of Gly-X-X motifs to form a collagen-like triple-helical structure; regulated at translational level by variable repeats (CAAAA); may overcome electrostatic repulsion between the hydrophobic region of Scl2 and hydrophobic cell surface	(83 –86)
GAS proteins binding to host ECM laminin (links to integrins α_mβ_n)	Lbp	Universal adhesin	(87)
	Lmb	Binds directly to laminin and contributes to GAS colonization and infection	(88)
	Lsp	Universal adhesin	(89)
	SclA/Scl1	Binds fibronectin and laminin; this ligand-switching mechanism between blood and tissue may augment GAS colonization and dissemination	(71)
	Shr	An anchorless adhesin binding to heme-containing proteins and ECM laminin, not fibronectin	(90)
	SpeB, extracellular cysteine protease	Binds tightly to bacterial surface and carries laminin-binding activity	(91)
GAS proteins binding to host plasminogen	M proteins	Certain M proteins bind plasminogen	(92)
	Plr/SDH/GAPDH	Binds plasminogen and plasmin	(92)
	SEN	Anchorless adhesin; mediates GAS adherence; binds plasminogen that allows GAS to invade deeper soft tissues	(93 –96)

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^{^a}

Abbreviations: Cpa, collagen type I-binding protein of group A streptococci; FbaA: fibronectin-binding protein of group A streptococci type A; FbaB, fibronectin-binding protein type B; Fbp54, fibronectin-binding protein 54; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HA, hyaluronic acid; Lbp, laminin-binding protein; Lmb, laminin-binding protein; Lsp, lipoprotein of Streptococcus pyogenes; LTA, lipoteichoic acid; Plr, streptococcal plasmin receptor; PrtF1, protein F1; PrtF2/PFBP, protein F2-binding protein; PrtH, M protein family protein H; SclA/Scl1 streptococcal collagen-like protein 1; SclB/Scl2, streptococcal collagen-like protein 2; SDH, surface dehydrogenase; SEN, streptococcal surface enolase; Sfbl, S. pyogenes fibronectin-binding protein I; SfbII, streptococcal fibronectin-binding protein class II; SfbX, fibronectin-binding protein X; Shr, streptococcal hemoprotein receptor; SOF, serum opacity factor; SpeB, streptococcal pyogenic exotoxin B.

Early in the 1980s, Grabovskaya et al. postulated that at least two mechanisms of GAS adherence, which are the lipoteichoic acid (LTA) and the pepsin-cleaved M protein, were involved in the attachment of GAS to HEp-2 epithelial cells (41). A decade later, Hasty et al. hypothesized “a two-step adhesion model” for GAS, and this model has become accepted (42). The model suggests that at least two successive steps with at least two different kinds of adhesins are involved in establishing firm GAS adherence (Table 1). The first step is a relatively weak and reversible adhesion that generally occurs when GAS attaches to most types of host cells. The binding of the hydrophobic components (i.e., LTA) of GAS to the hydrophobic domains of host cell surface molecules overcomes electrostatic repulsion and builds an initial loose attachment. This non-specific adhesion is further strengthened by the second step in the adhesion process (42). The second step is strong and irreversible. It is the formation of covalent bonds binding bacterial adhesins with counterpart cellular surface receptors of cells (42). Most GAS adhesins contain a sortase A motif (LPXTG) to anchor to the receptors on cell membranes. Nonetheless, the composition of host ECM varies between tissues. This composition mainly includes structural proteins (collagen, elastin, and keratin), adhesive glycoproteins (fibronectin, laminin, basement membranes, and vitronectin), proteoglycans, and matricellular proteins (97).

GAS enters into human cells by the GAS adhesin-ECM complexes interacting with the heterodimeric αβ integrins on host membranes. The host ECM proteins include, but are not limited to, fibronectin (binds α5β1), laminin (binds α1β1, α2β1, α3β1, α6β1, and α7β1), and collagen (binds α2β1) (98). GAS internalization is mainly mediated by surface M proteins and fibronectin-binding proteins (42). Of these, protein F1 and its allelic variant, SfbI, are crucial invasins (99 –102). M proteins serve as a bridge between the bacterial surface and fibronectin-binding integrins. When M1 serotype GAS invades human lung epithelial A549 cells, the binding of α5β1 integrin with M1-linked fibronectin efficiently enhances GAS internalization (39). Moreover, the interaction of the M protein and the human complement regulatory protein (membrane co-factor protein or CD46) aids in the adherence of GAS to keratinocytes during invasion. This CD46-mediated GAS invasion is fibronectin dependent (103). GAS also binds to laminins utilizing varying αβ integrins on the membrane of host cells (40, 102). Recently, Catton et al. identified CEACAM1 as a novel receptor for GAS adhesin R28 protein, which is epidemiologically correlated to puerperal sepsis outbreak (104). This interaction promotes bacterial adhesion to cervical cells, inhibition of epithelial wound repair, and impairment of innate immune responses, which are the events favoring the development of puerperal sepsis (104).

After establishing an effective GAS-ECM-integrin internalization, the rearrangement of the cytoskeletal structure occurs and triggers a cascade of cellular signaling that ultimately kills ingested GAS. The binding of integrin-mediated ECM-bound GAS indirectly activates cellular signaling. The mechanisms involved in this transduction include the phosphatidylinositol 3-kinase (PI3K)-dependent and PI3K-independent pathways, the Src family tyrosine kinases, and the Rho family GTPases RhoA, Rac, and Cdc42 (100, 105 –109). In brief, the clustered integrins activate integrin-linked kinase (ILK) through the binding to PI3K-phosphorylated membrane-bound phosphatidylinositol (110 –112). This activation initiates the small GTPases (RacI and Cdc42) and ILK to interact with paxillin (113). After that, a focal adhesion complex is formed with focal adhesion kinase (FAK), creating a docking site on Src kinase by autophosphorylation to phosphorylate paxillin (114). Then, the focal adhesion complex provides an anchor for actin polymerization and cytoskeleton rearrangement, allowing GAS internalization. Although the connections between ILK and the downstream FAK-Src and Rac-Cdc42 signaling need further clarification in GAS infection, the paxillin-FAK-Src pathway and the Rac-Cdc42 pathway have both been shown to be involved in GAS invasion (5, 109).

Following the GAS adhesion-induced signaling as described above, initial transforming growth factor-β, interleukin (IL)-1β, IL-6, IL-21, and IL-23-dependent differentiated Th17 cells induce the production of pro-inflammatory cytokines [IL-1α, IL-1β, IL-2, IL-6, interferon (IFN)-β, TNF-α, and RANTES/CCL5] (115 –119). In a synergic effect of IL-1α or IL-1β with IL-23 (120), the release of cytokines promotes the secretion of IL-17 from memory T cells. The nasal lymphoid tissue-associated IL-17 secreting T cells induced by GAS enhance the production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) that recruit neutrophils and macrophages (119).

GAS EVADES PHAGOCYTOSIS

Human cells conduct phagocytosis as a means of nutrient acquisition, homeostasis maintenance, and protection from pathogens (Fig. 1C). Depending on the efficiency of their phagocytosis, human cells are categorized as high-performance professional phagocytes (neutrophils, macrophages, monocytes, and dendritic cells) and low-performance non-professional phagocytes (epithelial cells, endothelial cells, and fibroblasts) (121, 122). When GAS invades non-professional cells, these infected cells initiate low-efficiency phagocytosis against GAS, accompanied by a bacterial killing process via autophagy and LC3-associated phagocytosis (Fig. 1D and 1E) (see the later sections for details). At the site of infection, the GAS is eventually eliminated by the professional phagocytic macrophages and neutrophils. To survive this phagocytosis, GAS evades phagocytosis through several mechanisms which are addressed below.

The early stage of phagocytosis: GAS circumvents phagocyte recruitment, abolishes antibody-mediated opsonization, and inhibits phagocyte uptake

GAS circumvents neutrophil/macrophage recruitment by producing the virulence factors SpeB, ScpA, and Plr/SDH/GAPDH to efficiently degrade complement-derived chemoattractants C3a and C5a (Fig. 2D) (19, 24 –27). The streptococcal secreted esterase (SsE) of GAS hinders the recruitment of neutrophils by hydrolyzing host platelet-activating factor (PAF), which serves as a phospholipid mediator for IL-1β-induced chemotaxis (123, 124). To interfere with CXC chemokine IL-8, an extracellular S. pyogenes cell envelope protease (SpyCEP) cleaves the C-terminal region of IL-8 and causes IL-8 inactivation, halting the rolling of neutrophils and their endothelial transmigration (125 –127). Moreover, a recent study reported an impairment of IL-8 secretion by macrophages when GAS streptolysin O (SLO) and nicotinamide-adenine dinucleotidase (NADase) dampen the Golgi network (128). Consequently, GAS manages to prolong the response time needed for hosts to initiate immune responses, helping GAS win the battle for survival.

GAS can be detected by cellular non-opsonic and opsonic receptors prior to phagocyte uptake. Once GAS is recognized by the cellular receptors, the subsequent cellular activation will stimulate the cells to generate reactive oxygen species (ROS), nitric oxide (NO), and inflammatory cytokines that eliminate GAS (Fig. 1C) (129). GAS also strategically prevents the binding of opsonic receptors by interfering with antibody-mediated opsonization. As well, GAS interferes with opsonin C3b formation, degradation, and deposition by producing GAS CEF, M proteins, Mrp, Plr/SDH/GAPDH, ScpA, and SpeB (Fig. 2B and 2C) (see Arms Race Between the Host Complement System and GAS Virulence Factors for details) (18 –24, 26, 27).

Aside from opsonophagocytosis, GAS evades phagocyte uptake by bacterial envelope obstruction and phagosome dysfunction. GAS cells that have mutations in the hyaluronic acid (HA) capsule and M protein are highly susceptible to phagocytic killing (45, 130). Additionally, the HA capsule of GAS contributes to the formation of mucoid colonies and the formation of biofilm (131). These observations suggest that the barrier-like HA capsule and M protein prevent phagocytes and opsonins from accessing the bacterial cell wall. Nonetheless, the functions of phagosome are affected by GAS. For instance, the oversized GAS-adhered ECM complex exceeds the capacity of the phagosome (2–5 µm) (132 –134). Through the binding of human fibrinogen to GAS M proteins, phagocytes overlook the ECM-M protein-masked GAS (135). During phagosome formation, the GAS streptococcal inhibitor of complement (SIC) disturbs actin rearrangement by interacting with the F-actin binding domain of the membrane-bound cytoskeleton linker protein ezrin (136). GAS virulence factor SpyA (S. pyogenes ADP-ribosylating toxin) has two functions: one is a C3-like arginine-specific ADP-ribosyltransferase and the other is a NAD-glycohydrolase. GAS SpyA covalently transfers NAD⁺-derived ADP-ribose to the acceptor protein, cytoskeletal structural actin, and interferes with phagosome formation (137 –139).

The middle stage of phagocytosis: GAS kills phagocytic cells

After internalizing inside phagocytes, GAS causes cell death via membrane leakage, vascular leakage, pyroptosis, and apoptosis. GAS β-hemolysin streptolysin S (SLS) and SLO are cytocidal proteins that form pores to disrupt cell membrane integrity and ion influx/efflux (Fig. 1C) (140 –142). Neutrophil-derived granule proteases cleave GAS M proteins that interact with host integrin-linked fibrinogen, causing the release of heparin binding proteins and vascular leakage (143, 144). Further evidence has shown that SLO causes its co-toxin NADase to translocate to cytosol, leading to NAD⁺ depletion, Golgi fragmentation, and cell death (128, 145, 146). Pyroptosis is another mechanism that causes cell death (Fig. 1G). GAS SLO and SpyA cause rapid NLRP3 inflammasome formation and caspase-1 dependent IL-1β secretion during GAS infection (Fig. 1F and 1G) (137 –139, 147 –149). Remarkably, GAS SpeB reportedly participates in the direct cleavage of gasdermin A (GSDMA) and modulates GSDMA-mediated inflammatory pyroptosis in keratinocytes during GAS infection (150, 151). GAS M1 proteins can cause pyroptosis in macrophages, and this pyroptosis then acts as a second signal for caspase-1 dependent NLRP3 inflammasome activation (152, 153). Other than pyroptosis, SLO and SpyA can activate caspase-3 in macrophages for apoptosis induction (149, 154), while cysteine protease SpeB cleaves and activates host matrix metalloproteinases to initiate apoptosis (155). Besides this, GAS SpeB induces mitochondrial dysfunction, resulting in a unique caspase-mediated apoptosis in epithelial and polymorphonuclear cells (156 –160).

The middle stage of phagocytosis: GAS counteracts host oxidative bursts and ROS-related metal acquisition

Internalized GAS stimulates phagocytes to generate oxidative and inflammatory responses during phagosome maturation (161, 162). Such oxidative bursts begin with host enzymes converting oxygen to oxidants and harmful ROS. In the GAS containing phagosomes (Fig. 1C), the host phagocytic NADPH oxidase 2 (NOX2, formerly gp91^phox) complex is recruited to the phagosome membrane. In the membrane, oxygen is reduced to a reactively unstable superoxide anion (O₂^•–) (163). The O₂^•– species is immediately converted to peroxide (H₂O₂), then to water (H₂O) and oxygen (O₂) by host catalase (CAT), and to toxic hypochlorous acid (HOCl) by host superoxide dismutase (SOD) and myeloperoxidase (MPO), respectively. This reaction also produces the ferrous ion (Fe²⁺)-mediated hydroxy radical (HO^•) through the Fenton reaction (164). The HOCl species possess strong bactericidal potential (164), while the associated free radicals (O₂^•– and HO^•) attack the nucleic acids, membranes, and proteins of invading pathogens (165). Indeed, catalase-negative GAS is limited in its ability to react against oxidative stressors (166). GAS expresses surface and secreted proteins that counteract ROS production (HA capsule, M protein, Mac-1, and Mac-2) (15, 167 –169), enzymatic ROS detoxification (AhpC, AhpF, GpoA, NoxA, and SodA) (170 –175), enzymatic repair of ROS-induced cell damage (HtrA and PolA1) (176, 177), resistance to the iron transport system of ROS (Dpr, MtsABC, PmtA, and Shr) (90, 170, 178 –183), and the expression of ROS regulatory proteins (metal and H₂O₂ regulator PerR, transcriptional regulators MtsR and Rgg/RopB, and two-component systems CiaRH and Ihk/Irr) (174, 181, 184 –189). GAS SclA also reportedly interferes with the release of host MPO (190). Nonetheless, special attention has been paid to the thioredoxin reducing systems (191). In these systems, reduced small molecules can react or reduce H₂O₂ directly via GAS GpoA (171). A recent study undertaken by Brouwer and colleagues discovered another glutathione-related strategy that GAS uses to survive host oxidative bursts (192). The abundant cytosolic glutathione diffuses through the membrane pores that have been formed by GAS SLO. GAS then hijacks the host antioxidant glutathione from the cytosol by using a GAS glutathione ABC transporter substrate binding protein (GshT) to reduce ROS stress. This strategy compensates the defect of GAS which does not possess de novo pathways for glutathione synthesis. Another ROS-mediated PerR regulation is metal homeostasis. Interestingly, some genes of the PerR regulon (adcRCB operon, adcA, phtY, rpsN2, and lmb-phtD genes) also have conserved AdcR motifs in their promoters, indicating that PerR and AdcR coordinate to modulate zinc acquisition systems during GAS infection (179). Consequently, GAS could resist host oxidative stress and may evade innate immune responses.

The late stage of phagocytosis: GAS resists host anti-microbial killing and escapes from neutrophil extracellular traps

During the maturation of phagosomes, they are fused with azurophilic and specific granules to form phagolysosomes. Engulfed GAS is then killed by the anti-microbial substances, i.e., cationic anti-microbial peptides (AMPs), cell wall-degrading lysozyme, and proteases, inside those phagolysosomes (Fig. 1C) (193, 194). Human cathelicidin LL-37 and α-defensins are positively charged AMPs, which are prone to being attracted to the negatively charged teichoic acids of the GAS cell wall. To impede this attraction, GAS reduces the net negative charge on the surface by expressing the dltABCD operon to produce proteins required for the D-alanylation of teichoic acids. Although the inactivation of the dltA gene in GAS M1 did not have much effect on phagocytic uptake by human neutrophils, this mutation caused the GAS dltA mutants to become more susceptible to AMP attack and lysozyme killing (195). Recent studies of cathelicidin LL-37 reveal new means by which GAS resists this AMP killing. The mucoid GAS exhibiting HA capsule may block LL-37 from access to cell walls (196), whereas the B-repeats and N-terminal domain of GAS M proteins bind to immature LL-37, interfering with LL-37 activity and blocking its access to the bacterial membrane (197, 198). Likewise, secreted GAS SIC binds to LL-37 to prevent bacterial killing (199). GAS cysteine protease SpeB and protease Ska also degrade LL-37 through direct cleavage and the activation of human plasmin, respectively (200, 201).

To efficiently control GAS infection and dissemination, professional phagocytic neutrophils convert themselves into neutrophil extracellular traps (NETs) (Fig. 1C), which make suicidal attacks on iGAS to restrain and kill them (202, 203). NETs are released from activated neutrophils and are composed of a mixture of granule proteins, anti-microbial peptides, and nuclear constituents (chromatin and histones). This process is also called NETosis, and it makes use of the NADPH oxidase (NOX2)-dependent and NOX2-independent pathways (204, 205). NOX2-dependent suicidal NETosis squeezes ruptured plasma membranes and DNA contents into extracellular space, which is a process that takes hours to complete. By contrast, NOX2-independent vital NETosis occurs in minutes, and it is induced by calcium accompanied by a histone modification of chromatin structure. The DNA-free neutrophils of NETs are still capable of phagocytosis and bacterial killing (204). However, GAS phage (a lysogen)-carrying streptodornase DNase (Sda1) degrades the DNA contents of NET, enabling the escape of GAS from NET entrapment (206). Besides the effects of GAS DNases, the interaction of the N-terminal portion of the M proteins with the histones prevents the histones’ anti-microbial activity (207). GAS SclA also promotes survival by protecting GAS from AMPs within NETs and by inhibiting the release of host MPO to suppress NET formation (190). Collectively, NETs play a critical role in neutrophil-mediated innate immunity (206), especially as a way to confine GAS to local infections (205, 208 –210).

SELECTIVE AUTOPHAGY (XENOPHAGY) AGAINST GAS INFECTION

After GAS enters cells, several kinds of cells, including epithelial cells, keratinocytes, and macrophages, have been shown to use a defense mechanism called xenophagy (Fig. 1D and 3), a selective autophagy that targets invading pathogens. The process of xenophagy is generally divided into several steps (211, 212). First, autophagy is initiated by inhibition of mammalian target of rapamycin complex 1 (mTORC1) followed by activation and translocation of the Unc-51-like kinase (ULK1) complex to the endoplasmic reticulum for phagophore formation. Then, the ULK1 complex recruits the PI3K complex to produce phosphatidylinositol 3-phosphate (PI3P) in the membrane for autophagosome biogenesis. The double membrane of the phagophore is further elongated by two ubiquitin-like conjugation systems, ATG12-ATG7-ATG10, and microtubule-associated protein 1 LC3-ATG7-ATG3 to generate the membrane-bound LC3-II. The phagophore decorated with LC3-II targets the ubiquitin or galectin-tagged invading pathogens by interacting with the autophagy adaptors. After completion of the autophagosomal membrane, autophagosome maturation further occurs through fusion with a lysosome, which contains enzymes to degrade the cargos. The process of autophagosome maturation is mediated by multiple soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) proteins (213, 214).

Fig 3 — Xenophagy induction and evasion during GAS infection. (A) The receptors for GAS invasion, D46-Cyt-1 and integrin α5β1, which form the complex with fibronectin (Fn) and GAS FbaA, induce initiation signaling by inhibiting mTORC1 and activate the components of phosphatidylinositol 3-kinase (PI3K) complex I, including beclin1 and VPS34 via interacting with scaffold protein GOPC, respectively. However, the PI3K-ATG14 and Rab1-mediated initiation signaling is inhibited by streptolysin (SLO) and NADase. The PI3K complex II, including beclin1, UVRAG, andVPS34, regulates vesicle fusion events, which is responsible for GAS invasion and GcAV-lysosome fusion, negatively regulated by NLRP4, NLRX1, and BcL-xL. GTPase Rab5 and Rab7 are also involved in GAS invasion. (B) Then the phagophore elongation and GcAV expansion are promoted by the following three mechanisms: (i) NLRP4-directing ARHGDI-Rho axis mediates the recruitment of Rab9A, bringing membrane source via actin; (ii) fusion of GcAV with recycling endosomes is mediated by several SNARE proteins, including Rab17 and STX6-VTI1B-vesicle-associated membrane protein (VAMP)3 complex, which are regulated by Rab GEF1; and (iii) Rab7 and Rab9a promote fusion of smaller GcAVs to become large GcAVs. (C) After invasion, GAS first exists in the endosome, then its pore-forming toxin, SLO, damages the endosome, leading to escape of GAS into the cytosol. The damaged endosomes and cytosolic GAS are further targeted by galectins or ubiquitin (Ub) for phagophore recruitment. There are three mechanisms which are reported for recognition of GAS-containing damaged endosomes: (i) Gal-8-parkin-Ub; (ii) Tollip-Gal-1 or Gal-7, which recruit autophagy receptors, nuclear dot protein 52 kDa (NDP52), NBR1, and P62; and (iii) Ca²⁺-dependent Ub-binding of TBC1 domain family member 9 (TBC1D9) activates TANK-binding kinase 1 (TBK1) to regulate recruitment of NDP52 to Ub/Rab35-targeting GAS. Guanylate-binding protein 1 (GBP1) also promotes phosphorylation of TBK1 to direct autophagy to GAS in damaged endosome. On the other hand, the cytosolic GAS is modified by S-guanylation, which is promoted by nitric oxide (NO)-produced 8-nitro-cGMP, followed by polyubiquitination. The Ub on GAS further binds to the autophagy receptors, including NDP52, NBR1, p62, for phagophore recruitment through binding to LC3. Rab7 and Rab23 also participate in GAS recognition through unknown mechanisms. However, the autophagy receptors can be bound to GAS protease, SpeB, for degradation. (D) Finally, the GcAVs would fuse with lysosomes to degrade bacteria. This fusion event is regulated by phosphorylation of LC3 by hippo kinases STK3/STK4 and VAMP8-Vit11b, whereas SLO and NADase not only prevent lysosome trafficking to GcAV and lysosome-GcAV fusion but also inhibit the acidification of phagolysosome, resulting in GAS multiplication.

GAS was first reported to induce selective autophagy for clearance in 2004 (215). The study conducted by Nakagawa et al. found that the intracellular GAS (M49 JRS4 strain) was surrounded by LC3 to form the GAS containing LC3-positive autophagosome-like vacuoles (GcAV), which would fuse with lysosomes in epithelial HeLa cells (215). Based on the time-lapse images, the morphology of GcAV is characterized from the beginning as a linear chain form, then several chain-like GcAVs assemble into grape-like GcAVs, followed by the boundary disappearing and coalescing into a single large GcAV (216). ATG5 and Rab7 were required for initial formation of smaller GcAV, and Rab9A is responsible for homotypic fusion of GcAVs (216, 217). These processes start from the endosome damage caused by pore-forming toxin SLO, which is indispensable for GAS escape from endosome to cytoplasm, followed by LC3 recruitment (215, 218). The GAS strains without SLO do not possess the ability to escape into the cytosol but are directly cleared by endosome maturation via lysosome fusion, which is regulated by Rab5 and Rab7 (218). Besides, Rab5 and Rab7 are also reported to participate in GAS invasion by endosome and autophagosome machinery targeting (218). This evidence revealed that GAS induces xenophagy; more studies clarify the mechanisms of GAS-induced xenophagy that could be classified into the four steps of xenophagy (Table 2).

TABLE 2.

Autophagic process in S. pyogenes^a

Autophagy step	Regulator	Function and mechanism	GAS strain	Cell line	Reference
Promotion of autophagy
Bacterial invasion	Rab7	Bacterial invasion, endosome maturation, autophagolysosome formation	M6 JRS4	Epithelial cells (HeLa)	(218)
Bacterial invasion	Rab5	Bacterial invasion, endosome fusion	M6 JRS4	Epithelial cells (HeLa)	(218)
Endosome damage	SLO	Endosome damage, escapes to cytoplasm	M6 JRS4	Epithelial cells (HeLa)	(215, 218)
Induction/initiation	CD46-Cty-1/GOPC pathway	Autophagy induction CD46-Cyt-1 link to VPS34/beclin1 via its interaction with scaffold protein GOPC	M6 (CD46 dependent), M49 (CD46 independent)	Epithelial cells (HeLa)	(219)
	FbaA-Fn-integrin α5β1	Activates beclin1 through the mammalian target of rapamycin-ULK1-beclin1 pathway	M1 SF370	Epithelial cells (Hep-2)	(220)
GcAV expansion	Rab7	GcAV formation	M6 JRS4	Epithelial cells (HeLa)	(216)
	Rab17	Supplies membrane for GcAV from recycling endosomes	M6 JRS4	Epithelial cells (HeLa)	(221)
	NLRP4	GcAV expansion NLRP4-ARHGDIA-Rho axis regulates ATG9A recruitment via actin to facilitate GcAV expansion	M6 JRS4	Epithelial cells (HeLa)	(222)
	STX6-VTI1B-VAMP3	Fusion of GcAV with recycling endosomes RABGEF1 mediates this fusion event by STX6-VTI1B-VAMP3 complex	M6 JRS4	Epithelial cells (HeLa)	(223)
Substrate targeting	Rab23	GAS targeting and GcAV formation	M6 JRS4	Epithelial cells (HeLa)	(217)
	nitric oxide	Lys63-linked polyubiquitination of S-quanylated GAS S-guanylation of GAS by 8-nitro-cGMP	M6 JRS4	Macrophages (RAW 264.7), Epithelial cells (HeLa, A549) and fibroblasts (MEF)	(224)
	SLO and SLS	Galectin-8 and ubiquitin recruitment	M3 188 and M6 JRS4	Keratinocytes (OKP7/bmi1/TERT)	(225)
	SLS alone	Galectin-8 recruitment	M3 188 and M6 JRS4	Keratinocytes (OKP7/bmi1/TERT)	(225)
	Tollip	Recruitment of several xenophagy receptors, galectin-1 and galectin-7 Directly interacts with galectin-7	M6 JRS4	Epithelial cells (HeLa, HaCaT)	(226)
	SLO and TBC1D9	ULK1 complex recruitment and autophagy initiation Regulates TBK1 through Ca²⁺ signaling	M6 JRS4	Epithelial cells (HeLa, HaCaT)	(227)
	Guanylate-binding protein 1	Directs xenophagy by promoting phosphorylated TBK-1 followed by p63 recruitment Interacts with TBK1	M6 JRS4	Epithelial cells (HeLa, A549)	(228)
Fusion with lysosome	Rab7	Autophagolysosome formation	M6 JRS4	Epithelial cells (HeLa)	(218)
	VAMP8 and Vti1b	Xenophagosome and lysosome fusion	M6 JRS4	Epithelial cells (HeLa, A549, and MCF7)	(229)
	Rab9A	GcAV fusion and enlargement, and lysosome fusion	M6 JRS4	Epithelial cells (HeLa)	(217)
	Hippo kinases STK3/STK4	Fusion of autophagosomes with lysosomes Phosphorylation of LC3 at Thr⁵⁰	M49 NZ131	Fibroblasts (MEF)	(230)
Inhibition in autophagy
GAS internalization	Bcl-xL	Inhibition of GAS internalization interaction with beclin1-UVRAG	M6 JRS4	Epithelial cells (HeLa)	(231)
	NLRX1	Inhibition of GAS internalization interaction with Becline-1-UVRAG	M6 JRS4	Epithelial cells (HeLa)	(232)
Induction/initiation	NLRP4	Negatively regulates autophagy initiation and endosome and autophagosome maturation Associates with beclin1 and VPS	M6	Epithelial cells (HeLa) and endothelial cells (HUVEC)	(233)
	SLO and NADase	Inhibits RAB1 and PIK3C3 complex-dependent autophagy	M6 JRS4	Epithelial cells (HeLa)	(234)
Substrate targeting	SpeB (M1T1 clone)	Evades autophagy and replicates in cytosol SpeB degrades ubiquitin-LC3 adaptor proteins (P62, NDP52, and NBR1)	M1T1 5448	Epithelial cells (HEp-2)	(235)
Fusion with lysosome	SLO and NADase	Inhibition of autophagosome and lysosome fusion	M3 188 and M6 JRS4	Keratinocytes (OKP7/bmi1/TERT)	(225)
	SLO	Prevents phagolysosome acidification	M1 854	Macrophages (THP-1)	(236)
	SLO	Ruptures GcAV and reduces lysosome association with GAS	M1T1 5448 and M49 NZ131	Macrophages (U937 and THP-1) and primary macrophages	(237)
	NADase	Inhibition of intracellular trafficking of GAS to lysosomes	M3 188	Keratinocytes (OKP7/bmi1/TERT)	(238)
	Bcl-xL	Suppression of autophagosome-lysosome fusion	M6 JRS4	Epithelial cells (HeLa)	(231)
	NLRX1	Suppression of autophagosome-lysosome fusion	M6 JRS4	Epithelial cells (HeLa)	(232)
Defective xenophagy and LC3-associated phagocytosis in endothelial cells
Substrate targeting	Ubiquitin	Insufficient acidification of autophagosomes in endothelial cells Defected NO-mediated ubiquitination	M49 NZ131	Endothelial cells (HMEC1) and epithelial cells (A549)	(239, 240)
Substrate targeting	Galectin-3	Blocks ubiquitin recruitment through inhibiting recruitment of galectin-8 and parkin	M49 NZ131	Endothelial cells (HMEC1) and epithelial cells (A549)	(241)
LAP induction and xenophagy inhibition	SLO and β1 integrin	Triggers LAPosome formation and inhibits xenophagy induction Induces NOX2/ROS pathway and inhibits mTORC-ULK1 signaling	M49 NZ131	Endothelial cells (HMEC1) and epithelial cells (A549)	(242)
Xenophagy induction and fusion with lysosome	NAD⁺ (induced by nicotinamide)	Increases GcAV trafficking to lysosome and acidification of GcAV (induces xenophagy) Increases NAD⁺ content and NAD⁺/NADH ratio	M49 NZ131	Endothelial cells (HMEC1) and epithelial cells (A549)	(243)
Xenophagy induction and lysosomal activity	VEGF^b	Promotes xenophagy and lysosomal activity Activates transcription factor EB by cAMP-IP3-Ca²⁺	M49 NZ131	Endothelial cells (HMEC1) and epithelial cells (A549)	(244)

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^{^a}

GAS proteins are underlined.

^{^b}

VEGF, vascular endothelial growth factor.

Xenophagy induction/initiation

The first step is xenophagy induction (Fig. 3A). Two cell surface receptors participate in initiation of GAS-induced xenophagy. The first one is CD46-Cyt-1, which is the GAS-binding receptor, linked to the autophagosome formation complex VPS34/beclin1 by the scaffold protein GOPC (219). The other is integrin α5β1, which is bound by FbaA of M1 GAS strain SF370 through fibronectin, the ligand of integrin α5β1, leading to mTORC1 inactivation and ULK1 dephosphorylation. Then, beclin1 is phosphorylated to activate VPS34 kinase for Rab7 recruitment to ultimately promote autophagosome maturation (220). Moreover, the nucleotide-binding and oligomerization domain-like receptors (NLRs), which are the main pattern recognition receptors (PRRs) for inflammasome activation, have been identified to negatively regulate autophagic initiation by interacting with beclin1 via the NACHT domain (233). NLRP4 was further shown to be transiently recruited to GAS-containing phagosomes accompanied with beclin1 dissociation at the early time point of infection, and depletion of NLRP4 increases LC3-positive GcAV, suggesting NLRP4 as a sensor permits the beclin1-initiated xenophagy (233). Owing to the physical interactions of NLRP4 with the class C vacuolar protein-sorting complex, including VPS11, VPS16, and VPS18, studies show that NLRP4 also contains the ability to inhibit endosome and autophagosome maturation (233). Another NLR, NLRX1, also binds to beclin1 and UVRAG to inhibit endocytosis-mediated GAS invasion (232). The other protein Bcl-xL, the well-known anti-apoptotic protein, possesses similar mechanisms to prevent GAS internalization by interacting with beclin1-UVRAG (231). However, knockout of beclin1 or ATG14, the two components of PI3K complex, does not influence GcAV formation, suggesting the existence of a PI3K-independent pathway for autophagy induction upon GAS infection (231). The study of Toh et al. further supported this idea, showing that GAS SLO and NADase inhibit starvation-induced and ubiquitinated protein aggregate-induced autophagy, respectively, which are widely recognized as PI3K-dependent pathways. Although the PI3K complex is activated during GAS infection, NADase inhibits the recruitment of the PI3K complex and Rab1 to GAS (234).

Elongation and GcAV expansion

After initiation of autophagic signaling, the isolation membrane elongates followed by GcAV expansion (Fig. 3B). Since NLRP4 was reported as a sensor for GcAV initiation, people were curious about its function in GcAV formation, other than the role as a gatekeeper (233). Through using the NACHT domain of NLRP4 as a bait, the screening of yeast two-hybrid systems identified multiple NLRP4-interacting proteins. Among the candidate proteins, Rho GDP dissociation inhibitor A (RHGDIA) strongly colocalized with both NLRP4 and LC3. After NLRP4 recruits RHGDIA, RHGDIA would further recruit Rho GTPases to GcAV. Then, RHGDIA disassociates from the complex via its Tyr156 phosphorylation to release activated Rho proteins. Because Rho family proteins are the critical regulator of the actin cytoskeleton, which is required for ATG9A trafficking to a phagophore, the study also demonstrated that the RHGDIA-Rho axis regulates ATG9A recruitment by actin to facilitate phagophore elongation and GcAV expansion (222). Furthermore, the membrane source of GcAV is clarified by staining the markers of membrane organelles, including endoplasmic reticulum, mitochondria, Golgi apparatus, and endosomes, showing that the GcAV membrane originates from the recycling endosomes, indicated by the marker, transferrin receptor (221). The fusion of recycling endosome with GcAVs is mediated by Rab17 and its GFP, Rabex-5, as well as the SNARE complex, syntaxin 6-VTI1B-vesicle-associated membrane protein (VAMP)3, which is regulated by Rab GEF1 (222).

Substrate targeting

After autophagy initiation signaling and phagophore formation, the invading bacteria would be further recognized by the phagophore membrane through two main tags, ubiquitin and galectins (Fig. 3C) (245 –248). The ubiquitination of the bacterial surface or damaged membrane is generally processed by the recruitment of E3 ligases, including LUBAC, LRSAM1, ARIH, HOIP1, and more (249 –252). Upon GAS infection, ubiquitination of GAS is mediated by NO-produced endogenous 8-nitro-cGMP, which modifies cysteine residues by S-guanylation, promoting Lys63-linked ubiquitination of GAS (224). Then, the ubiquitin will further bind to the ubiquitin-binding region of autophagy receptors/adaptors, including p62 (also called sequestosome, SQSTM1), neighbor of BRCA1 (NBR1), nuclear dot protein 52 kDa (NDP52), and optineurin, which are further phosphorylated via TANK-binding kinase 1 (TBK1) or other kinases, to facilitate LC3 interaction with the LC3-interacting region of autophagy receptors for phagophore recruitment and autophagosome formation (246, 247, 252 –255). However, the upstream signaling for TBK1 activation had not been fully understood until a recent study discovered the Ca²⁺-binding protein TBC1 domain family member 9 (TBC1D9), which contains UBD and Ca²⁺-binding motif. The TBC1D9 binds to ubiquitin-coating GAS and cytosolic Ca²⁺, which is increased by SLO-mediated pore formation, to recruit and activate TBK1, followed by subsequent recruitment of NDP52 and ULK1 complexes (227). Furthermore, guanylate-binding protein 1 has just been reported to interact with TBK1, which self-regulates its phosphorylation for p62 recruitment to GAS for autophagosome formation. In contrast to the M6 JRS4 strain of GAS, which triggers efficient autophagy machinery in the epithelial cells mentioned above (Table 2), the globally disseminated GAS M1T1 strain can evade autophagy and thus multiply efficiently in the cytosol of epithelial cells through the SpeB-mediated degradation of autophagy receptors, NDP52, p62, and NBR1 (235). In macrophages, the GAS M1T1 strain can also survive and replicate in the cytoplasm in a SLO-dependent manner, despite half of the cytosolic GAS co-localizing with ubiquitin and p62 (237).

In addition to ubiquitin-mediated recognition, galectins are other critical tags binding to the glycans exposed on the damaged bacteria-containing endosomes/phagosomes for recruitment of autophagy machinery via interacting with autophagy receptors (248, 256, 257). In keratinocyte, the endosome damage caused by SLS alone induces glycan exposure for galectin-8 recruitment, followed by xenophagy recognition in a ubiquitin-independent manner. Actions of SLS coupled with SLO produce sufficient damage for both ubiquitin and galectin-8 recognition of cytosolic bacteria and damaged endosomes (258). The recruited galectin-8 interacts with E3 ligase, parkin, for subsequent ubiquitin recruitment in epithelial cells, whereas this mechanism is blocked in endothelial cells owing to higher galectin-3 expression and recruitment in endothelial cells (241). Moreover, galectin-1 and galectin-7 are also recruited to endosomes prior to GAS escape to the cytosol in epithelial cells, by the autophagy receptor Tollip, which also recruits other autophagy receptors, including NBR1, TAX1BP1, and NDP52, promoting restriction of GAS replication by xenophagy (226).

Autophagosome maturation and fusion with lysosomes

Once the cytosolic materials are sequestered into isolated double membrane vesicles and formed as completed autophagosomes, the newly formed autophagosomes undergo a process called “autophagosome maturation.” The process of maturation includes fusion of an autophagosome with endosomes and lysosomes to form an amphisome and autolysosome, respectively, which is mediated by SNARE complexes, tethering proteins, and Rab GTPases (Fig. 3D) (213, 214). The acidification of autophagolysosome mediated by V-ATPase, which is indispensable for the activity of degrative enzymes from the lysosome, is involved in the process of maturation (214, 259, 260). The SNARE proteins can be functionally divided into v-SNARE, the ones associated with the vesicles, and t-SNARE, indicating the SNARE proteins associated with the target compartment. Vesicle-associated membrane protein 8 (VAMP8) is identified as the v-SNAREs interacting with the t-SNARE, Vit1b, to promote GcAV and lysosome fusion (229). In contrast, the other t-SNAREs, Syntaxin 7 and Syntaxin 8, are not involved in this fusion event (229). The Rab7 GTPase and its guanine nucleotide exchange factor and the homotypic fusion and protein sorting (HOPS) complex, which is the tethering complex that promotes t-SNARE complex assembly, act together to promote fusion of autophagosome with lysosomes (261, 262). Although the role of HOPS has not been clarified in the fusion of a GcAV and lysosomes, Rab7 was responsible for this fusion event (218). Rab9a is also recruited to GcAV after maturation for GcAV enlargement and fusion with lysosomes (217). Moreover, phosphorylation of LC3 at threonine 50 by the hippo kinases STK3/STK4 also contributes to the fusion of GcAV with lysosomes (230). For fine regulation of the GcAV-lysosome fusion, Bcl-xL and NLRX1 play roles as the negative regulators in the host cells (231, 232).

In order to escape from the degradation of autophagolysosomes, pathogens develop multiple mechanisms to inhibit the fusion event or acidification of the autophagolysosome (213). GAS uses its SLO and the co-toxin NADase to prevent fusion of GcAV with lysosomes or inhibit acidification of autophagolysosomes or phagolysosomes in different cell types (213, 225, 236 –239). Because SLO is required for NADase translocation to the cytosol, it is difficult to distinguish the effects of NADase from SLO. To resolve this problem, Sharma et al. demonstrated that NADase from the M1T1 strain alone prevents the intracellular trafficking of lysosome to GAS, promoting GAS survival by delivery of the active NADase fused to an amino-terminal fragment of anthrax toxin lethal factor (LFn-NADase), which allows NADase to translocate to the cytosol without the help of SLO (238).

DEFECTIVE XENOPHAGY AND LC3-ASSOCIATED PHAGOCYTOSIS in GAS-INFECTED ENDOTHELIAL CELLS

Compared to the effective xenophagy mechanisms for GAS clearance in epithelial cells, endothelial cells, which, given intrusion of bacteria into the bloodstream for their dissemination throughout the body, potentially leading to fatal disease, have been found to be intrinsically defective in xenophagy (Fig. 1E and 4) (239, 240). In epithelial cells, GAS is surrounded by an LC3-positive double membrane followed by fusion with lysosomes and proper acidification as indicated by Lysotracker, the acidic organelle labeling dye, resulting in GAS elimination. However, in endothelial cells, the LC3-positive GAS containing compartments show a single membrane by correlative light-electron microscopy, and these compartments cannot be stained by Lysotracker despite successful fusion with lysosomes as indicated by the marker LAMP-1; therefore, GAS multiplies efficiently in endothelial cells (239, 240). The study by Lu et al. reveals that the main reason for the deficiency of xenophagosome formation is less efficient ubiquitin coating on GAS in endothelial cells, followed by lower recruitment of ULK1, ATG14, and ATG9, which are the proteins specific for the xenophagy machinery (239, 240). Two underlying mechanisms have been identified to contribute to lower ubiquitin recruitment: the first one is a reduced level of NO-induced 8-nitrogen-cGMP, which enhances ubiquitin-coating of GAS (224, 240); second, the expression and recruitment of galectin-3 to GAS are higher in endothelial cells, subsequently blocking the recruitment of galectin-8-parkin-ubiquitn, which is highly recruited to GAS in epithelial cells (241).

Fig 4 — The mechanism of LC3-associated phagocytosis (LAP) and the strategy for xenophagy induction in endothelial cells upon GAS infection. GAS infection in endothelial cells mainly induces LC3-associated phagocytosis via ROS production, which is induced by SLO-1 integrin-NOX2 axis. Meanwhile, ROS inhibits xenophagy initiation signaling by activating both PI3K-AKT and MEK1/2-ERK pathways, resulting in enhanced phosphorylation of mTORC1 for downregulation of ULK1 activity. Although the LAPosomes can fuse with lysosomes, as indicated by LAMP1-positive signal, they cannot be acidified efficiently, leading to bacterial multiplication. Moreover, in endothelial cells, the level of ubiquitination of GAS-containing damaged endosomes is deficient, resulting from higher recruitment of galectin-3 (Gal-3) for blocking Gal-8-parkin-ubiquitin, as well as lower induction and production of 8-nitro-cGMP. Treatment with nicotinamide and vascular endothelial growth factor (VEGF) enhances xenophagy for GAS elimination through increasing ND + content and ratio of NAD+/NADH and driving transcription factor EB (TFEB)-mediated autophagic and lysosomal biogenesis.

Owing to the characteristics of LC3-positive single membrane bacteria-containing vacuoles and lower recruitment of specific autophagic proteins in endothelial cells, it was speculated that these compartments are LC3-associated phagosomes (LAPosomes), but not xenophagosomes (242). Although these two pathways share the similar conjugation systems for LC3 decoration, the initiation mechanisms are quite different (263, 264). LAP is activated via receptor-mediated phagocytosis followed by recruiting Rubicon- and UVRAG-containing PI3K complexes for PI3P deposition on a LAPosome. PI3P and Rubicon further mediate recruitment and stabilization of the NOX2 complex, respectively, for ROS production. PI3P and ROS promote the recruitment of the downstream conjugation system, ATG12-ATG5-ATG16L and ATG4-ATG7-ATG3 (265). Cheng et al. showed that most of the LC3-associated GAS-containing compartments in endothelial cells are single membrane with NOX2 recruitment but not ULK1, the specific protein involved in canonical autophagy induction, indicating GAS infection mainly triggers the LAP pathway in endothelial cells, although these LAPosomes cannot be acidified efficiently through an undefined mechanism (242). Inhibition of NOX2 and ROS significantly converts the LAP pathway to a conventional xenophagy pathway, indicated by reduction of NOX2 recruitment, enhancement of ULK1 recruitment, and mTORC1 inactivation through downregulating PI3K-AKT and MEK1/2-ERK signaling, and double membrane formation, resulting in sufficient acidification and GAS elimination (242). The SLO of GAS is further shown as the ROS inducer inducing LAP by the β1 integrin, coherent with the finding in Listeria monocytogenes showing that a β2 integrin, Mac-1, is the receptor for L. monocytogenes-induced LAP activation (242, 266).

Treatment with nicotinamide, a vitamin B3 derivative, and vascular endothelial growth factor (VEGF) has been identified as a potential strategy to enhance autophagic and lysosomal activity to eliminate GAS in endothelial cells (243, 244). Nicotinamide treatment increases NAD⁺ content and the NAD⁺:NADH ratio for promotion of autophagic activity, including the trafficking of GAS containing vacuoles to lysosomes and acidification of GAS-containing vacuoles (243). Mutation of GAS NADase, which is a hydrolase participating in consumption of NAD⁺, leads GAS to lose growth ability in endothelial cells (243). On the other hand, administration of VEGF amplifies activation of transcription factor EB, which is a master transcription factor driving the genes involved in lysosomal biogenesis through the cAMP-IP₃-Ca²⁺-dependent pathway, boosting lysosomal function for GAS clearance (244). In the mouse with bacteremia and the patients with GAS-induced sepsis, the serum VEGF levels are low, and the administration of VEGF attenuated mortality in the GAS sepsis mouse model (244). Taken together, these results provide the mechanisms of GAS evasion from autophagy in endothelial cells, which may result in dissemination of GAS into the bloodstream.

INFLAMMATION AND INFLAMMOSOME ACTIVATION

Inflammation

Inflammation is commonly induced by bacterial infections as a host-protective characteristic via recruiting immune cells and counteracting bacterial colonization, replication, and dissemination. Invasive GAS infection was characterized by robust inflammation responses that may lead to cytokine storms and severe tissue injury, as well as initiation of autoimmune reactions (267, 268).

PRR-mediated signaling is a well-characterized mechanism for activation of inflammatory responses through recognizing a variety of damage-associated molecular patterns/pathogen-associated molecular patterns (PAMP) (Fig. 1F) (269, 270). GAS, as a Gram-positive bacterium, can activate the PRR, toll-like receptor (TLR)2 on cell surfaces through sensing the cell wall components, lipopeptides, LTA, and peptidoglycan extracellularly (271). Once GAS internalizes into the cell and exists in endosomes or lysosomes, TLR8, TLR9 in human, and TLR13 in mice, which locate to these compartments, will be activated after detecting bacterial RNA or unmethylated bacterial CpG DNA (272 –275). Recently, Movert et al. further identified that GAS-derived c-di-AMP as a PAMP can diffuse into macrophages via SLO pores and activate STING to induce type I IFN response. However, the enzymatically active NADase inhibits STING-mediated IFN production (276). Subsequently, the activated PRRs drive activation of several transcription factors, including nuclear factor kappa B (NF-κB), to trigger pro-inflammatory gene expression such as TNF, IL-6, and pro-IL-1β, which mediate recruitment and activation of macrophages and neutrophils. On the other hand, TLRs and other unknown mechanisms induce type I IFN production to inhibit neutrophil infiltration to balance inflammation responses (277 –279). Besides, PAMPs and PRRs also induce the crucial signals for priming the inflammasome activation, which has been identified as a critical mechanism in GAS-induced inflammation (280, 281).

NLRP3 inflammasome-dependent pathway

Inflammasomes are cytosolic supramolecular protein complexes, mainly operating by caspase-1-dependent release of pro-inflammatory cytokines IL-1β and IL-18. Inflammasomes are composed of three kinds of proteins, which are sensors, adaptors, and effectors. Among “canonical” inflammasomes, several sensors have been identified, including the NLR family pyrin domain-containing 1, NLRP3 and NLRP6, the NLR family CARD domain-containing 4, the absence in melanoma 2, the pyrin, and the recently discovered CARD8, which initiate nucleation of inflammasomes upon stimuli of different activating signals (280, 282). Based on the present studies, NLRP3 is the only canonical inflammasome that is reported to be involved in GAS infection (147, 149, 153). NLRP3 is a tripartite protein that consists of three domains, an amino-terminal pyrin domain (PYD), a central NACHT domain, and a carboxyl terminal leucine-rich repeat domain (LRR) (283). The NACHT domain contains the ATPase activity triggering NLRP3 self-oligomerization and function (284). On the contrary, the LRR domain is responsible for the autoinhibitory effect by folding back to the NACHT domain (285). The PYD domain of NLRP3 would further interact with the N-terminal PYD domain of the adaptor ASC, followed by the carboxyl-terminal caspase recruitment domain (CARD)-CARD domain interactions between ASC and the effector caspase-1, leading to the self-cleavage and activation of caspase-1. The activated caspase-1 further cleaves pro-IL-1β and pro-IL-18 into IL-1β and IL-18, and cleaves a pore-forming protein, gasdermin D (GSDMD) into the amino-terminal domain, inserting into the membrane and forming the pores for IL-1β and IL-18 secretion, as well as pyroptosis induction (286, 287).

The inflammasome activation is finely regulated by signal 1 for priming and signal 2 for activation. The priming signals were provoked via several ligands and receptors binding, including PAMPs-TLRs, TNF-TNF receptor, IL-1β-IL-1β receptor type 1, and IFN-β-IFN-α/β receptor, to upregulate expression of inflammasome components by NF-κB gene transcription (283). The priming signals can also manipulate post-translational modification of NLRP3, such as phosphorylation, ubiquitination, and SUMOylation, which also participate in negative regulation of NLRP3 activity under different signals for fine manipulation of an inflammasome, which has been heavily reviewed elsewhere (283, 288, 289). After the priming step, the activation signals for NLRP3 inflammasome assembly and activation of the following events as mentioned above are mainly induced by K⁺ efflux with few exceptions. Nigericin, a K⁺/H ⁺ ionophore, and ATP-activated P2X purinoceptor 7 (P2X7, a ligand-gated ion-channel) have been known to regulate K⁺ efflux for IL-1β maturation and release (290 –292). However, GAS-induced NLRP3 activation is TLR signaling-independent and P2X7 receptor-independent, but dependent on the pore-forming ability of SLO for K⁺ efflux and NF-κB activation via an undefined mechanism (147). Moreover, GAS NADase inhibited P2X7 receptor-mediated release of IL-1β (293). NADase, which is a secreted virulence factor, can translocate into the cytosol from the extracellular space or phagolysosome via a SLO-dependent mechanism to hydrolyze NAD⁺ intracellularly, leading to depletion of energy stores (146, 294). Surprisingly, although an NADase mutant strain (nga G330D) significantly reduced inflammasome-mediated IL-1β release, a phagocytosis inhibitor did not attenuate GAS-triggered IL-1β production, indicating the inhibitory effect of NADase on inflammasome activation is independent of cytosolic translocation but reliant on its extracellular activity (295).

M proteins, the most abundant GAS surface proteins, including M1, M2, M3, M4, M5, and M6, were reported to trigger IL-1β signaling. M1 serves as the second signal to induce caspase-1-independent NLRP3 activation under priming with different TLR agonists, such as the TLR4 agonist-lipopolysaccharide, TLR2 agonists-peptidoglycan, LTA, and Pam3CSK4, as well as the TLR7 and TLR8 agonist R848. Internalization of M1 via clathrin-mediated endocytosis is required for inflammasome activation (153). In a mouse model, soluble M1 was sufficient to induce IL-1β activation for host immunity against pathogens in the early phase of infection by intraperitoneal injection of GAS, whereas in systemic infection, M1-activated IL-1β release and pyroptosis enhanced tissue injury (153). Other than M proteins, several virulence factors also participated in NLRP3-mediated inflammasome activation, including GAS ADP-ribosyltransferase toxin, SpyA, SLS, and SLO, which are cytolysins with pore-forming activity (147, 149, 296). The pore-forming ability is indispensable for inflammasome activation. Though the total abrogation of the pore-formation activity of SLO diminished the pyroptosis and IL-1β production, partially active SLO mutant strains enhanced inflammasome activation (148). On the other hand, SLO counteracts promoting ubiquitination and degradation of pro-IL-1β, implying SLO-regulated IL-1β release and simultaneous degradation may contribute to optimal circumstances for infection (258, 297).

NLRP3 inflammasome-independent pathway

In addition to NLRP3-dependent inflammasome activation, GAS virulence factors also target molecules for IL-1β maturation via an NLRP3-independent mechanism. The cysteine protease SpeB was identified to cleave pro-IL-1β extracellularly to produce biologically active IL-1β for an increase of NO synthase activity in vascular smooth muscle cells and cause cell death, suggesting a possible mechanism for SpeB-caused myocardial necrosis (298). Recently, Johnson et al. revealed that SpeB also cleaves constitutively secreted pro-IL-18 from keratinocytes to induce pro-inflammatory response during GAS infection (299). In addition, SpeB cleaves pro-IL-1β within the cells without involvement of caspase-1 to trigger IL-1β maturation and release. The co-localization of SpeB and IL-1β in the cell, and the IL-1β signaling induction after co-expression of SpeB and pro-IL-1β, strongly support the intracellular role of SpeB in IL-1β signaling. Furthermore, SpeB degrades the canonical inflammasome-activating virulence factors, SLO and SpyA. These findings explain how IL-1β restricts invasive GAS infection independently of the inflammasome in vivo (300). In contrast to the above-mentioned studies showing that IL-1β has a host-protective effect, in the murine nasopharynx, which is a primary site for GAS colonization, infection, and transmission, SpeB-activated IL-1β recruits neutrophils to diminish microbiota, promoting GAS colonization (301).

CELL DEATH RELATED TO GAS INTERFERENCE

Decades ago, GAS was found to induce programmed cell death, especially apoptosis (160, 302). Several mechanisms were identified to activate apoptosis by at least five streptococcal virulence factors, including SpeB, SLO, NADase, Plr/SDH/GAPDH, and serine/threonine phosphatase (SP-STP) (4). The roles of apoptosis during bacterial infection, including GAS infection in epithelial cells, are considered host defense strategies to delete infected cells and restrict bacterial proliferation and dissemination (4, 303). Nevertheless, apoptosis may help bacteria escape from phagocytotic killing when it happens in phagocytic cells (4, 157). Recently, another kind of programmed cell death caught people’s eyes, which was called pyroptosis, induced by inflammasome-activated gasdermins (Fig. 1G). Several kinds of bacteria, including Burkholderia, Francisella, Salmonella, and Shigella, have been reported to activate inflammasome- or non-inflammasome-driven gasdermin activation, resulting in pyroptosis and potentially anti-bacterial effects, such as direct binding to bacterial membranes for bacterial killing, enhancement of localized immune responses, mitochondrial interactions, and intracellular bacteria exclusion (304).

Compared to other bacteria, which activate gasdermins via indirect signaling, such as several pore-forming toxins facilitating K⁺ efflux and Ca⁺ influx, triggering inflammasome activation, GAS SpeB was reported to directly target GSDMA, followed by IL-1β maturation and pyroptosis (Fig. 1G) (150, 151, 304, 305). GSDMA belongs to the family of pore-forming proteins-gasdermins, which are encoded by five paralogous genes (GSDMA, GSDMB, GSDMC, GSDMD, and GSDME) in humans and identified to be the final executor of inflammasome-mediated cytokine secretion and lytic cell death-pyroptosis through inserting into the plasma membrane for pore formation (306, 307). In canonical and non-canonical inflammasome pathways, GSDMD is cleaved by caspase-1 and caspase-11/caspase-4/caspase-5, respectively, to generate an N-terminal fragment followed by insertion into plasma membrane and assembly in the membrane to form the pores (286, 287, 308). Following these findings, the studies of gasdermins are blossoming, and various proteases which are specific to different gasdermins have been clarified, except GSDMA (307). Until recently, GAS cysteine protease SpeB was reported to cleave GSDMA directly (Fig. 1G) (150, 151). GSDMA displays mostly in skin epithelial cells and the upper gastrointestinal tract. Through a whole genome CRISPR-CAS9 screening, single-guide RNAs targeting GSDMA dramatically blocked intracellular SpeB-induced lytic cell death in skin epithelial cells (150). Moreover, host anti-GAS immunity is significantly lost in GSDMA-deficient mice (150). Co-expression of GSDMA and SpeB in the cells produced the N-terminal fragments, which disappeared after cysteine protease inhibitor E64 treatment. In vitro cleavage assay further confirmed that recombinant GSDMA was cleaved by SpeB (150). In keratinocytes, SpeB also cleaves GSDMA, leading to GSDMA-dependent pyroptosis (151). Ultimately, GSDMA-deficient mice develop uncontrolled systemic bacteria dissemination and death after GAS infection, demonstrating that GSDMA-driven pyroptosis restricts local inflammation and causes elimination of the pathogens.

CONCLUDING REMARKS

Group A Streptococcus is a clinically important human pathogen that possesses abundant virulence factors, which grant it the power to hinder immune responses. Until the present, treating invasive infections and developing vaccines to prevent GAS infections have been extremely difficult. However, over the last couple of decades, the growing body of research on GAS that has been undertaken by various teams has begun to shed light on the mechanisms of GAS pathogenesis. Yet, it is still uncertain how exactly GAS applies its virulence factors to adapt to stressful environments inside host cells. Also, the responses of the host cells that interact with GAS during infection are obscure. To illuminate these host-GAS interactions, studies using GAS-invading human epithelial and endothelial cells have provided excellent models to examine the effect of GAS virulence factors during phagocytosis, autophagy, and LC3-associated phagocytosis. For instance, GAS SLO, NADase, and SpeB play significant roles in manipulating host cellular signaling and innate immune responses during the dissemination, inflammation, and the GSDMA-dependent pyroptosis of cell death. The findings from those investigations allow researchers to postulate hypotheses on the mechanisms of interspecies cross-talk, a feature that has not been accurately explained by complex animal infection models. Nonetheless, future research on GAS-host interaction during infection can be explored more intensively using 3D human organoids in combination with state-of-the-art multiomics, single-cell sequencing, or dual RNA long-read sequencing technologies. Those advanced approaches will lead to the discovery of the genetic determinants of GAS-human interaction, as well as the differential RNA isoform expression profiles and epigenetic modifications of hosts during different GAS infectious events. This will help our understanding of the strategies used by GAS to counteract innate immune responses and will ultimately facilitate the development of new therapeutic regimens to treat and prevent invasive GAS infections.

ACKNOWLEDGMENTS

We thank Drs. Robert Jonas, Benfang Lei, and Ryan Holroyd for helpful comments and for editing the manuscript.

This study was supported by the National Science and Technology Council, Taiwan (NSTC 111-2320-B-468-005, NSTC 111-2811-B-468-001, NSTC 112-2320-B-468-005, and NSTC 112-2811-B-468-001).

Biographies

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Marcia Shu-Wei Su is currently serving as a postdoctoral researcher at Asia University and National Yang Ming Chiao Tung University in Taiwan, where she studies invasive group A Streptococcus and the innate immune responses of its hosts. Her research interests are primarily focused on understanding the intricate interaction between microbes and their specific hosts, the effects of these interactions, and their subsequent implications for host health. Marcia has an academic background in microbiology and acquired her PhD from the University of Alberta in Canada. She has gained professional research training from the Pennsylvania State University and the Jackson Laboratory for Genomic Medicine in the United States. Her research expertise includes studying the impact of pathogenic and probiotic bacteria on hosts and the effect of maternal age on the transmission of human mitochondrial DNA.

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Yi-Lin Cheng is an immunologist, cell biologist, and microbiologist. She obtained her PhD from the Institute of Basic Medical Sciences, National Cheng Kung University (NCKU), Tainan, Taiwan, in 2016. After graduating, she studied the defective xenophagy of group A Streptococcus in endothelial cells as a postdoctoral fellow under the supervision by Dr. Jiunn-Jong Wu and Dr. Yee-Shin Lin. Then in 2019 she joined Ivan Dikic’s group in Goethe University, Frankfurt, Germany, as a postdoctoral researcher investigating the role of intracellular LPS in ER-phagy. In August 2022, she started her career in Institute of Basic Medical Sciences, NCKU, Tainan, Taiwan, as an assistant professor and continuously study on host-pathogen interactions in bacterial and viral infection.

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Yee-Shin Lin is an immunologist and microbiologist. She obtained her PhD from Department of Microbiology and Immunology, Temple University, Philadelphia, USA. She started her career as a lecturer in the Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University (NCKU), Tainan, Taiwan. Over the years, Dr. Lin advanced her academic positions from Associate Professor to Professor, and ultimately Distinguished Professor. She is now honored as Professor Emeritus in the same institute. In her 34-year career, she has mentored 48 MS students, 17 PhD or MD/PhD students (including dual degree PhD of NCKU and Osaka University and of NCKU and University of Malaya), and 6 postdoctoral fellows. Her primary research interests lie in understanding the interaction between pathogens and host immune responses, with a particular emphasis on group A Streptococcus and dengue disease. Both areas are significant public health concerns and need more effective therapeutic and preventive strategies.

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Jiunn-Jong Wu is a microbiologist. Currently, he is a chaired professor, and dean of the College of Medical and Health Sciences, Asia University, Taichung, Taiwan. Professor Wu obtained his PhD from the Department of Microbiology and Immunology at Temple University, Philadelphia, USA. He undertook postdoctoral training in the Department of Molecular Experimental Medicine, Research Institute of Scripps Clinic, La Jolla, USA. Prof. Wu is an expert in medical microbiology, and he also is a fellow of the American Academy of Microbiology. In 2015, he was elected as dean of the College of Biomedical Science and Engineering, National Yang Ming University, Taipei, Taiwan. He has supervised 48 MS, 14 PhD and 10 postdoctoral fellows in the past 30 years. His major research interests included bacteria and host interaction, bacterial pathogenesis, mechanisms of antimicrobial resistance, and microbiome.

Contributor Information

Yee-Shin Lin, Email: yslin1@mail.ncku.edu.tw.

Jiunn-Jong Wu, Email: jjwu1019@asia.edu.tw.

Corrella S. Detweiler, University of Colorado Boulder, Boulder, Colorado, USA

REFERENCES

1. Carapetis JR, Steer AC, Mulholland EK, Weber M. 2005. The global burden of group A streptococcal diseases. Lancet Infect Dis 5:685–694. doi: 10.1016/S1473-3099(05)70267-X [DOI] [PubMed] [Google Scholar]
2. Brouwer S, Rivera-Hernandez T, Curren BF, Harbison-Price N, De Oliveira DMP, Jespersen MG, Davies MR, Walker MJ. 2023. Pathogenesis, epidemiology and control of group A Streptococcus infection. Nat Rev Microbiol 21:619. doi: 10.1038/s41579-023-00939-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
3. Efstratiou A, Lamagni T. 2022. Epidemiology of Streptococcus pyogenes. In Ferretti JJ, Stevens DL, Fischetti VA (ed), Streptococcus pyogenes: basic biology to clinical manifestations, 2nd ed. Oklahoma City (OK). [Google Scholar]
4. Pancholi V. 2019. Group A Streptococcus-mediated host cell signaling. Microbiol Spectr 7. doi: 10.1128/microbiolspec.GPP3-0021-2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
5. Wang B, Cleary PP. 2019. Intracellular invasion by Streptococcus pyogenes: invasins, host receptors, and relevance to human disease. Microbiol Spectr 7. doi: 10.1128/microbiolspec.GPP3-0049-2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Wilkening RV, Langouët-Astrié C, Severn MM, Federle MJ, Horswill AR. 2023. Identifying genetic determinants of Streptococcus pyogenes-host interactions in a murine intact skin infection model. Cell Rep 42:113332. doi: 10.1016/j.celrep.2023.113332 [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Kachroo P, Eraso JM, Olsen RJ, Zhu L, Kubiak SL, Pruitt L, Yerramilli P, Cantu CC, Ojeda Saavedra M, Pensar J, Corander J, Jenkins L, Kao L, Granillo A, Porter AR, DeLeo FR, Musser JM. 2020. New pathogenesis mechanisms and translational leads identified by multidimensional analysis of necrotizing myositis in primates. mBio 11:e03363-19. doi: 10.1128/mBio.03363-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
8. Okumura CYM, Nizet V. 2014. Subterfuge and sabotage: evasion of host innate defenses by invasive Gram-positive bacterial pathogens. Annu Rev Microbiol 68:439–458. doi: 10.1146/annurev-micro-092412-155711 [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. 2019. New insights into the immune functions of complement. Nat Rev Immunol 19:503–516. doi: 10.1038/s41577-019-0168-x [DOI] [PMC free article] [PubMed] [Google Scholar]
10. Syed S, Viazmina L, Mager R, Meri S, Haapasalo K. 2020. Streptococci and the complement system: interplay during infection, inflammation and autoimmunity. FEBS Lett 594:2570–2585. doi: 10.1002/1873-3468.13872 [DOI] [PubMed] [Google Scholar]
11. Dunkelberger JR, Song W-C. 2010. Complement and its role in innate and adaptive immune responses. Cell Res 20:34–50. doi: 10.1038/cr.2009.139 [DOI] [PubMed] [Google Scholar]
12. Nordenfelt P, Waldemarson S, Linder A, Mörgelin M, Karlsson C, Malmström J, Björck L. 2012. Antibody orientation at bacterial surfaces is related to invasive infection. J Exp Med 209:2367–2381. doi: 10.1084/jem.20120325 [DOI] [PMC free article] [PubMed] [Google Scholar]
13. Honda-Ogawa M, Sumitomo T, Mori Y, Hamd DT, Ogawa T, Yamaguchi M, Nakata M, Kawabata S. 2017. Streptococcus pyogenes endopeptidase O contributes to evasion from complement-mediated bacteriolysis via binding to human complement factor C1q. J Biol Chem 292:4244–4254. doi: 10.1074/jbc.M116.749275 [DOI] [PMC free article] [PubMed] [Google Scholar]
14. Collin M, Svensson MD, Sjöholm AG, Jensenius JC, Sjöbring U, Olsén A. 2002. EndoS and SpeB from Streptococcus pyogenes inhibit immunoglobulin-mediated opsonophagocytosis. Infect Immun 70:6646–6651. doi: 10.1128/IAI.70.12.6646-6651.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
15. Lei B, DeLeo FR, Hoe NP, Graham MR, Mackie SM, Cole RL, Liu M, Hill HR, Low DE, Federle MJ, Scott JR, Musser JM. 2001. Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis. Nat Med 7:1298–1305. doi: 10.1038/nm1201-1298 [DOI] [PubMed] [Google Scholar]
16. Su YF, Chuang WJ, Wang SM, Chen WY, Chiang-Ni C, Lin YS, Wu JJ, Liu CC. 2011. The deficient cleavage of M protein-bound IgG by IdeS: insight into the escape of Streptococcus pyogenes from antibody-mediated immunity. Mol Immunol 49:134–142. doi: 10.1016/j.molimm.2011.08.002 [DOI] [PubMed] [Google Scholar]
17. Sjögren J, Okumura CYM, Collin M, Nizet V, Hollands A. 2011. Study of the IgG endoglycosidase EndoS in group A streptococcal phagocyte resistance and virulence. BMC Microbiol 11:120. doi: 10.1186/1471-2180-11-120 [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Aghababa H, Ting YT, Pilapitiya D, Loh JMS, Young PG, Proft T. 2022. Complement evasion factor (CEF), a novel immune evasion factor of Streptococcus pyogenes. Virulence 13:225–240. doi: 10.1080/21505594.2022.2027629 [DOI] [PMC free article] [PubMed] [Google Scholar]
19. Honda-Ogawa M, Ogawa T, Terao Y, Sumitomo T, Nakata M, Ikebe K, Maeda Y, Kawabata S. 2013. Cysteine proteinase from Streptococcus pyogenes enables evasion of innate immunity via degradation of complement factors. J Biol Chem 288:15854–15864. doi: 10.1074/jbc.M113.469106 [DOI] [PMC free article] [PubMed] [Google Scholar]
20. Kuo CF, Lin YS, Chuang WJ, Wu JJ, Tsao N. 2008. Degradation of complement 3 by streptococcal pyrogenic exotoxin B inhibits complement activation and neutrophil opsonophagocytosis. Infect Immun 76:1163–1169. doi: 10.1128/IAI.01116-07 [DOI] [PMC free article] [PubMed] [Google Scholar]
21. Kuo CF, Tsao N, Cheng MH, Yang HC, Wang YC, Chen YP, Lin KJ. 2015. Application of the C3-binding motif of streptococcal pyrogenic exotoxin B to protect mice from invasive group A streptococcal infection. PLoS One 10:e0117268. doi: 10.1371/journal.pone.0117268 [DOI] [PMC free article] [PubMed] [Google Scholar]
22. Carlsson F, Sandin C, Lindahl G. 2005. Human fibrinogen bound to Streptococcus pyogenes M protein inhibits complement deposition via the classical pathway. Mol Microbiol 56:28–39. doi: 10.1111/j.1365-2958.2005.04527.x [DOI] [PubMed] [Google Scholar]
23. Courtney HS, Hasty DL, Dale JB. 2006. Anti-phagocytic mechanisms of Streptococcus pyogenes: binding of fibrinogen to M-related protein. Mol Microbiol 59:936–947. doi: 10.1111/j.1365-2958.2005.04977.x [DOI] [PubMed] [Google Scholar]
24. Lynskey NN, Reglinski M, Calay D, Siggins MK, Mason JC, Botto M, Sriskandan S. 2017. Multi-functional mechanisms of immune evasion by the streptococcal complement inhibitor C5a peptidase. PLoS Pathog 13:e1006493. doi: 10.1371/journal.ppat.1006493 [DOI] [PMC free article] [PubMed] [Google Scholar]
25. McKenna S, Aylward F, Miliara X, Lau RJ, Huemer CB, Giblin SP, Huse KK, Liang M, Reeves L, Pearson M, Xu Y, Rouse SL, Pease JE, Sriskandan S, Kagawa TF, Cooney J, Matthews S. 2023. The protease associated (PA) domain in ScpA from Streptococcus pyogenes plays a role in substrate recruitment. Biochim Biophys Acta Proteins Proteom 1871:140946. doi: 10.1016/j.bbapap.2023.140946 [DOI] [PubMed] [Google Scholar]
26. Cleary PP, Prahbu U, Dale JB, Wexler DE, Handley J. 1992. Streptococcal C5a peptidase is a highly specific endopeptidase. Infect Immun 60:5219–5223. doi: 10.1128/iai.60.12.5219-5223.1992 [DOI] [PMC free article] [PubMed] [Google Scholar]
27. Terao Y, Yamaguchi M, Hamada S, Kawabata S. 2006. Multifunctional glyceraldehyde-3-phosphate dehydrogenase of Streptococcus pyogenes is essential for evasion from neutrophils. J Biol Chem 281:14215–14223. doi: 10.1074/jbc.M513408200 [DOI] [PubMed] [Google Scholar]
28. Berends ETM, Dekkers JF, Nijland R, Kuipers A, Soppe JA, van Strijp JAG, Rooijakkers SHM. 2013. Distinct localization of the complement C5b-9 complex on Gram-positive bacteria. Cell Microbiol 15:1955–1968. doi: 10.1111/cmi.12170 [DOI] [PubMed] [Google Scholar]
29. Akesson P, Sjöholm AG, Björck L. 1996. Protein SIC, a novel extracellular protein of Streptococcus pyogenes interfering with complement function. J Biol Chem 271:1081–1088. doi: 10.1074/jbc.271.2.1081 [DOI] [PubMed] [Google Scholar]
30. Fernie-King BA, Seilly DJ, Willers C, Würzner R, Davies A, Lachmann PJ. 2001. Streptococcal inhibitor of complement (SIC) inhibits the membrane attack complex by preventing uptake of C567 onto cell membranes. Immunology 103:390–398. doi: 10.1046/j.1365-2567.2001.01249.x [DOI] [PMC free article] [PubMed] [Google Scholar]
31. Agrahari G, Liang Z, Glinton K, Lee SW, Ploplis VA, Castellino FJ. 2016. Streptococcus pyogenes employs strain-dependent mechanisms of C3b inactivation to inhibit phagocytosis and killing of bacteria. J Biol Chem 291:9181–9189. doi: 10.1074/jbc.M115.704221 [DOI] [PMC free article] [PubMed] [Google Scholar]
32. Fujita T, Nussenzweig V. 1979. The role of C4-binding protein and β1H in proteolysis of C4b and C3b. J Exp Med 150:267–276. doi: 10.1084/jem.150.2.267 [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Gigli I, Fujita T, Nussenzweig V. 1979. Modulation of the classical pathway C3 convertase by plasma proteins C4 binding protein and C3b inactivator. Proc Natl Acad Sci U S A 76:6596–6600. doi: 10.1073/pnas.76.12.6596 [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Ermert D, Shaughnessy J, Joeris T, Kaplan J, Pang CJ, Kurt-Jones EA, Rice PA, Ram S, Blom AM. 2015. Virulence of group A Streptococci is enhanced by human complement inhibitors. PLoS Pathog 11:e1005043. doi: 10.1371/journal.ppat.1005043 [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Ermert D, Laabei M, Weckel A, Mörgelin M, Lundqvist M, Björck L, Ram S, Linse S, Blom AM. 2019. The molecular basis of human IgG-mediated enhancement of C4b-binding protein recruitment to group A Streptococcus. Front Immunol 10:1230. doi: 10.3389/fimmu.2019.01230 [DOI] [PMC free article] [PubMed] [Google Scholar]
36. Ermert D, Weckel A, Magda M, Mörgelin M, Shaughnessy J, Rice PA, Björck L, Ram S, Blom AM. 2018. Human IgG increases virulence of Streptococcus pyogenes through complement evasion. J Immunol 200:3495–3505. doi: 10.4049/jimmunol.1800090 [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Ly D, Taylor JM, Tsatsaronis JA, Monteleone MM, Skora AS, Donald CA, Maddocks T, Nizet V, West NP, Ranson M, Walker MJ, McArthur JD, Sanderson-Smith ML. 2014. Plasmin(ogen) acquisition by group A Streptococcus protects against C3b-mediated neutrophil killing. J Innate Immun 6:240–250. doi: 10.1159/000353754 [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Vercellotti GM, McCarthy JB, Lindholm P, Peterson PK, Jacob HS, Furcht LT. 1985. Extracellular matrix proteins (fibronectin, laminin, and type IV collagen) bind and aggregate bacteria. Am J Pathol 120:13–21. [PMC free article] [PubMed] [Google Scholar]
39. Cue D, Dombek PE, Lam H, Cleary PP. 1998. Streptococcus pyogenes serotype M1 encodes multiple pathways for entry into human epithelial cells. Infect Immun 66:4593–4601. doi: 10.1128/IAI.66.10.4593-4601.1998 [DOI] [PMC free article] [PubMed] [Google Scholar]
40. Hynes RO. 1992. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25. doi: 10.1016/0092-8674(92)90115-s [DOI] [PubMed] [Google Scholar]
41. Grabovskaya KB, Totoljan AA, Rýc M, Havlícek J, Burova LA, Bícová R. 1980. Adherence of group A streptococci to epithelial cells in tissue culture. Zentralbl Bakteriol A 247:303–314. [PubMed] [Google Scholar]
42. Hasty DL, Ofek I, Courtney HS, Doyle RJ. 1992. Multiple adhesins of streptococci. Infect Immun 60:2147–2152. doi: 10.1128/iai.60.6.2147-2152.1992 [DOI] [PMC free article] [PubMed] [Google Scholar]
43. Beachey EH, Ofek I. 1976. Epithelial cell binding of group A streptococci by lipoteichoic acid on fimbriae denuded of M protein. J Exp Med 143:759–771. doi: 10.1084/jem.143.4.759 [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Ryan PA, Pancholi V, Fischetti VA. 2001. Group A streptococci bind to mucin and human pharyngeal cells through sialic acid-containing receptors. Infect Immun 69:7402–7412. doi: 10.1128/IAI.69.12.7402-7412.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
45. Dale JB, Washburn RG, Marques MB, Wessels MR. 1996. Hyaluronate capsule and surface M protein in resistance to opsonization of group A streptococci. Infect Immun 64:1495–1501. doi: 10.1128/iai.64.5.1495-1501.1996 [DOI] [PMC free article] [PubMed] [Google Scholar]
46. Wessels MR, Moses AE, Goldberg JB, DiCesare TJ. 1991. Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci. Proc Natl Acad Sci U S A 88:8317–8321. doi: 10.1073/pnas.88.19.8317 [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Schrager HM, Albertí S, Cywes C, Dougherty GJ, Wessels MR. 1998. Hyaluronic acid capsule modulates M protein-mediated adherence and acts as a ligand for attachment of group A Streptococcus to CD44 on human keratinocytes. J Clin Invest 101:1708–1716. doi: 10.1172/JCI2121 [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Cywes C, Stamenkovic I, Wessels MR. 2000. CD44 as a receptor for colonization of the pharynx by group A Streptococcus. J Clin Invest 106:995–1002. doi: 10.1172/JCI10195 [DOI] [PMC free article] [PubMed] [Google Scholar]
49. Cywes C, Wessels MR. 2001. Group A Streptococcus tissue invasion by CD44-mediated cell signalling. Nature 414:648–652. doi: 10.1038/414648a [DOI] [PubMed] [Google Scholar]
50. Beachey EH, Courtney HS. 1987. Bacterial adherence: the attachment of group A streptococci to mucosal surfaces. Rev Infect Dis 9:S475–S481. doi: 10.1093/clinids/9.supplement_5.s475 [DOI] [PubMed] [Google Scholar]
51. Courtney HS, von Hunolstein C, Dale JB, Bronze MS, Beachey EH, Hasty DL. 1992. Lipoteichoic acid and M protein: dual adhesins of group A streptococci. Microb Pathog 12:199–208. doi: 10.1016/0882-4010(92)90054-r [DOI] [PubMed] [Google Scholar]
52. Okada N, Liszewski MK, Atkinson JP, Caparon M. 1995. Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of the group A Streptococcus. Proc Natl Acad Sci U S A 92:2489–2493. doi: 10.1073/pnas.92.7.2489 [DOI] [PMC free article] [PubMed] [Google Scholar]
53. Giannakis E, Jokiranta TS, Ormsby RJ, Duthy TG, Male DA, Christiansen D, Fischetti VA, Bagley C, Loveland BE, Gordon DL. 2002. Identification of the streptococcal M protein binding site on membrane cofactor protein (CD46). J Immunol 168:4585–4592. doi: 10.4049/jimmunol.168.9.4585 [DOI] [PubMed] [Google Scholar]
54. Abbot EL, Smith WD, Siou GPS, Chiriboga C, Smith RJ, Wilson JA, Hirst BH, Kehoe MA. 2007. Pili mediate specific adhesion of Streptococcus pyogenes to human tonsil and skin. Cell Microbiol 9:1822–1833. doi: 10.1111/j.1462-5822.2007.00918.x [DOI] [PubMed] [Google Scholar]
55. Manetti AGO, Zingaretti C, Falugi F, Capo S, Bombaci M, Bagnoli F, Gambellini G, Bensi G, Mora M, Edwards AM, Musser JM, Graviss EA, Telford JL, Grandi G, Margarit I. 2007. Streptococcus pyogenes pili promote pharyngeal cell adhesion and biofilm formation. Mol Microbiol 64:968–983. doi: 10.1111/j.1365-2958.2007.05704.x [DOI] [PubMed] [Google Scholar]
56. Rouchon CN, Ly AT, Noto JP, Luo F, Lizano S, Bessen DE. 2017. Incremental contributions of FbaA and other impetigo-associated surface proteins to fitness and virulence of a classical group A streptococcal skin strain. Infect Immun 85:e00374-17. doi: 10.1128/IAI.00374-17 [DOI] [PMC free article] [PubMed] [Google Scholar]
57. Hytönen J, Haataja S, Finne J. 2003. Streptococcus pyogenes glycoprotein-binding strepadhesin activity is mediated by a surface-associated carbohydrate-degrading enzyme, pullulanase. Infect Immun 71:784–793. doi: 10.1128/IAI.71.2.784-793.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
58. Terao Y, Kawabata S, Kunitomo E, Murakami J, Nakagawa I, Hamada S. 2001. Fba, a novel fibronectin-binding protein from Streptococcus pyogenes, promotes bacterial entry into epithelial cells, and the fba gene is positively transcribed under the Mga regulator. Mol Microbiol 42:75–86. doi: 10.1046/j.1365-2958.2001.02579.x [DOI] [PubMed] [Google Scholar]
59. Jaffe J, Natanson-Yaron S, Caparon MG, Hanski E. 1996. Protein F2, a novel fibronectin-binding protein from Streptococcus pyogenes, possesses two binding domains. Mol Microbiol 21:373–384. doi: 10.1046/j.1365-2958.1996.6331356.x [DOI] [PubMed] [Google Scholar]
60. Rocha CL, Fischetti VA. 1997. Identification and characterization of a new protein from Streptococcus pyogenes having homology with fibronectin and fibrinogen binding proteins. Adv Exp Med Biol 418:737–739. doi: 10.1007/978-1-4899-1825-3_173 [DOI] [PubMed] [Google Scholar]
61. Rocha CL, Fischetti VA. 1999. Identification and characterization of a novel fibronectin-binding protein on the surface of group A streptococci. Infect Immun 67:2720–2728. doi: 10.1128/IAI.67.6.2720-2728.1999 [DOI] [PMC free article] [PubMed] [Google Scholar]
62. Terao Y, Kawabata S, Nakata M, Nakagawa I, Hamada S. 2002. Molecular characterization of a novel fibronectin-binding protein of Streptococcus pyogenes strains isolated from toxic shock-like syndrome patients. J Biol Chem 277:47428–47435. doi: 10.1074/jbc.M209133200 [DOI] [PubMed] [Google Scholar]
63. Kreikemeyer B, Klenk M, Podbielski A. 2004. The intracellular status of Streptococcus pyogenes: role of extracellular matrix-binding proteins and their regulation. Int J Med Microbiol 294:177–188. doi: 10.1016/j.ijmm.2004.06.017 [DOI] [PubMed] [Google Scholar]
64. Courtney HS, Dale JB, Hasty DI. 1996. Differential effects of the streptococcal fibronectin-binding protein, FBP54, on adhesion of group A streptococci to human buccal cells and HEp-2 tissue culture cells. Infect Immun 64:2415–2419. doi: 10.1128/iai.64.7.2415-2419.1996 [DOI] [PMC free article] [PubMed] [Google Scholar]
65. Kawabata S, Kunitomo E, Terao Y, Nakagawa I, Kikuchi K, Totsuka K, Hamada S. 2001. Systemic and mucosal immunizations with fibronectin-binding protein FBP54 induce protective immune responses against Streptococcus pyogenes challenge in mice. Infect Immun 69:924–930. doi: 10.1128/IAI.69.2.924-930.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
66. Cue D, Lam H, Cleary PP. 2001. Genetic dissection of the Streptococcus pyogenes M1 protein: regions involved in fibronectin binding and intracellular invasion. Microb Pathog 31:231–242. doi: 10.1006/mpat.2001.0467 [DOI] [PubMed] [Google Scholar]
67. Frick IM, Crossin KL, Edelman GM, Björck L. 1995. Protein H-a bacterial surface protein with affinity for both immunoglobulin and fibronectin type III domains. EMBO J 14:1674–1679. doi: 10.1002/j.1460-2075.1995.tb07156.x [DOI] [PMC free article] [PubMed] [Google Scholar]
68. Cue D, Southern SO, Southern PJ, Prabhakar J, Lorelli W, Smallheer JM, Mousa SA, Cleary PP. 2000. A nonpeptide integrin antagonist can inhibit epithelial cell ingestion of Streptococcus pyogenes by blocking formation of integrin α5β1-fibronectin-M1 protein complexes. Proc Natl Acad Sci U S A 97:2858–2863. doi: 10.1073/pnas.050587897 [DOI] [PMC free article] [PubMed] [Google Scholar]
69. Pancholi V, Fischetti VA. 1992. A major surface protein on group A streptococci is a glyceraldehyde-3-phosphate-dehydrogenase with multiple binding activity. J Exp Med 176:415–426. doi: 10.1084/jem.176.2.415 [DOI] [PMC free article] [PubMed] [Google Scholar]
70. Jin H, Song YP, Boel G, Kochar J, Pancholi V. 2005. Group A streptococcal surface GAPDH, SDH, recognizes uPAR/CD87 as its receptor on the human pharyngeal cell and mediates bacterial adherence to host cells. J Mol Biol 350:27–41. doi: 10.1016/j.jmb.2005.04.063 [DOI] [PubMed] [Google Scholar]
71. Caswell CC, Oliver-Kozup H, Han R, Lukomska E, Lukomski S. 2010. Scl1, the multifunctional adhesin of group A Streptococcus, selectively binds cellular fibronectin and laminin, and mediates pathogen internalization by human cells. FEMS Microbiol Lett 303:61–68. doi: 10.1111/j.1574-6968.2009.01864.x [DOI] [PMC free article] [PubMed] [Google Scholar]
72. Hanski E, Caparon M. 1992. Protein F, a fibronectin-binding protein, is an adhesin of the group A Streptococcus Streptococcus pyogenes. Proc Natl Acad Sci U S A 89:6172–6176. doi: 10.1073/pnas.89.13.6172 [DOI] [PMC free article] [PubMed] [Google Scholar]
73. Talay SR, Valentin-Weigand P, Jerlström PG, Timmis KN, Chhatwal GS. 1992. Fibronectin-binding protein of Streptococcus pyogenes: sequence of the binding domain involved in adherence of streptococci to epithelial cells. Infect Immun 60:3837–3844. doi: 10.1128/iai.60.9.3837-3844.1992 [DOI] [PMC free article] [PubMed] [Google Scholar]
74. Talay SR, Zock A, Rohde M, Molinari G, Oggioni M, Pozzi G, Guzman CA, Chhatwal GS. 2000. Co-operative binding of human fibronectin to Sfbl protein triggers streptococcal invasion into respiratory epithelial cells. Cell Microbiol 2:521–535. doi: 10.1046/j.1462-5822.2000.00076.x [DOI] [PubMed] [Google Scholar]
75. Kreikemeyer B, Talay SR, Chhatwal GS. 1995. Characterization of a novel fibronectin-binding surface protein in group A streptococci. Mol Microbiol 17:137–145. doi: 10.1111/j.1365-2958.1995.mmi_17010137.x [DOI] [PubMed] [Google Scholar]
76. Jeng A, Sakota V, Li Z, Datta V, Beall B, Nizet V. 2003. Molecular genetic analysis of a group A Streptococcus operon encoding serum opacity factor and a novel fibronectin-binding protein, SfbX. J Bacteriol 185:1208–1217. doi: 10.1128/JB.185.4.1208-1217.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
77. Rakonjac JV, Robbins JC, Fischetti VA. 1995. DNA sequence of the serum opacity factor of group A streptococci: identification of a fibronectin-binding repeat domain. Infect Immun 63:622–631. doi: 10.1128/iai.63.2.622-631.1995 [DOI] [PMC free article] [PubMed] [Google Scholar]
78. Courtney HS, Hasty DL, Li Y, Chiang HC, Thacker JL, Dale JB. 1999. Serum opacity factor is a major fibronectin-binding protein and a virulence determinant of M type 2 Streptococcus pyogenes. Mol Microbiol 32:89–98. doi: 10.1046/j.1365-2958.1999.01328.x [DOI] [PubMed] [Google Scholar]
79. Oehmcke S, Podbielski A, Kreikemeyer B. 2004. Function of the fibronectin-binding serum opacity factor of Streptococcus pyogenes in adherence to epithelial cells. Infect Immun 72:4302–4308. doi: 10.1128/IAI.72.7.4302-4308.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
80. Podbielski A, Woischnik M, Leonard BA, Schmidt KH. 1999. Characterization of nra, a global negative regulator gene in group A streptococci. Mol Microbiol 31:1051–1064. doi: 10.1046/j.1365-2958.1999.01241.x [DOI] [PubMed] [Google Scholar]
81. Kreikemeyer B, Nakata M, Oehmcke S, Gschwendtner C, Normann J, Podbielski A. 2005. Streptococcus pyogenes collagen type I-binding Cpa surface protein. Expression profile, binding characteristics, biological functions, and potential clinical impact. J Biol Chem 280:33228–33239. doi: 10.1074/jbc.M502896200 [DOI] [PubMed] [Google Scholar]
82. Lukomski S, Nakashima K, Abdi I, Cipriano VJ, Ireland RM, Reid SD, Adams GG, Musser JM. 2000. Identification and characterization of the scl gene encoding a group A Streptococcus extracellular protein virulence factor with similarity to human collagen. Infect Immun 68:6542–6553. doi: 10.1128/IAI.68.12.6542-6553.2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
83. Humtsoe JO, Kim JK, Xu Y, Keene DR, Höök M, Lukomski S, Wary KK. 2005. A streptococcal collagen-like protein interacts with the α2β1 integrin and induces intracellular signaling. J Biol Chem 280:13848–13857. doi: 10.1074/jbc.M410605200 [DOI] [PubMed] [Google Scholar]
84. Caswell CC, Barczyk M, Keene DR, Lukomska E, Gullberg DE, Lukomski S. 2008. Identification of the first prokaryotic collagen sequence motif that mediates binding to human collagen receptors, integrins α2β1 and α11β1. J Biol Chem 283:36168–36175. doi: 10.1074/jbc.M806865200 [DOI] [PMC free article] [PubMed] [Google Scholar]
85. Lukomski S, Nakashima K, Abdi I, Cipriano VJ, Shelvin BJ, Graviss EA, Musser JM. 2001. Identification and characterization of a second extracellular collagen-like protein made by group A Streptococcus: control of production at the level of translation. Infect Immun 69:1729–1738. doi: 10.1128/IAI.69.3.1729-1738.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]
86. Squeglia F, Bachert B, De Simone A, Lukomski S, Berisio R. 2014. The crystal structure of the streptococcal collagen-like protein 2 globular domain from invasive M3-type group A Streptococcus shows significant similarity to immunomodulatory HIV protein gp41. J Biol Chem 289:5122–5133. doi: 10.1074/jbc.M113.523597 [DOI] [PMC free article] [PubMed] [Google Scholar]
87. Terao Y, Kawabata S, Kunitomo E, Nakagawa I, Hamada S. 2002. Novel laminin-binding protein of Streptococcus pyogenes, Lbp, is involved in adhesion to epithelial cells. Infect Immun 70:993–997. doi: 10.1128/IAI.70.2.993-997.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
88. Wahid RM, Yoshinaga M, Nishi J, Maeno N, Sarantuya J, Ohkawa T, Jalil AM, Kobayashi K, Miyata K. 2005. Immune response to a laminin-binding protein (Lmb) in group A streptococcal infection. Pediatr Int 47:196–202. doi: 10.1111/j.1442-200x.2005.02038.x [DOI] [PubMed] [Google Scholar]
89. Elsner A, Kreikemeyer B, Braun-Kiewnick A, Spellerberg B, Buttaro BA, Podbielski A. 2002. Involvement of Lsp, a member of the LraI-lipoprotein family in Streptococcus pyogenes, in eukaryotic cell adhesion and internalization. Infect Immun 70:4859–4869. doi: 10.1128/IAI.70.9.4859-4869.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
90. Dahesh S, Nizet V, Cole JN. 2012. Study of streptococcal hemoprotein receptor (Shr) in iron acquisition and virulence of M1T1 group A Streptococcus. Virulence 3:566–575. doi: 10.4161/viru.21933 [DOI] [PMC free article] [PubMed] [Google Scholar]
91. Hytönen J, Haataja S, Gerlach D, Podbielski A, Finne J. 2001. The SpeB virulence factor of Streptococcus pyogenes, a multifunctional secreted and cell surface molecule with strepadhesin, laminin-binding and cysteine protease activity. Mol Microbiol 39:512–519. doi: 10.1046/j.1365-2958.2001.02269.x [DOI] [PubMed] [Google Scholar]
92. Walker MJ, McArthur JD, McKay F, Ranson M. 2005. Is plasminogen deployed as a Streptococcus pyogenes virulence factor? Trends Microbiol 13:308–313. doi: 10.1016/j.tim.2005.05.006 [DOI] [PubMed] [Google Scholar]
93. Pancholi V, Fischetti VA. 1998. α-enolase, a novel strong plasmin(ogen) binding protein on the surface of pathogenic streptococci. J Biol Chem 273:14503–14515. doi: 10.1074/jbc.273.23.14503 [DOI] [PubMed] [Google Scholar]
94. Pancholi V, Fontan P, Jin H. 2003. Plasminogen-mediated group A streptococcal adherence to and pericellular invasion of human pharyngeal cells. Microb Pathog 35:293–303. doi: 10.1016/j.micpath.2003.08.004 [DOI] [PubMed] [Google Scholar]
95. Siemens N, Patenge N, Otto J, Fiedler T, Kreikemeyer B. 2011. Streptococcus pyogenes M49 plasminogen/plasmin binding facilitates keratinocyte invasion via integrin-integrin-linked kinase (ILK) pathways and protects from macrophage killing. J Biol Chem 286:21612–21622. doi: 10.1074/jbc.M110.202671 [DOI] [PMC free article] [PubMed] [Google Scholar]
96. Sumitomo T, Nakata M, Higashino M, Yamaguchi M, Kawabata S. 2016. Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions. Sci Rep 7:20069. doi: 10.1038/srep20069 [DOI] [PMC free article] [PubMed] [Google Scholar]
97. Mecham RP. 2012. Overview of extracellular matrix. Curr Protoc Cell Biol Chapter 10:10. doi: 10.1002/0471143030.cb1001s57 [DOI] [PubMed] [Google Scholar]
98. Dupuy AG, Caron E. 2008. Integrin-dependent phagocytosis: spreading from microadhesion to new concepts. J Cell Sci 121:1773–1783. doi: 10.1242/jcs.018036 [DOI] [PubMed] [Google Scholar]
99. Berkower C, Ravins M, Moses AE, Hanski E. 1999. Expression of different group A streptococcal M proteins in an isogenic background demonstrates diversity in adherence to and invasion of eukaryotic cells. Mol Microbiol 31:1463–1475. doi: 10.1046/j.1365-2958.1999.01289.x [DOI] [PubMed] [Google Scholar]
100. Dombek PE, Cue D, Sedgewick J, Lam H, Ruschkowski S, Finlay BB, Cleary PP. 1999. High-frequency intracellular invasion of epithelial cells by serotype M1 group A streptococci: M1 protein-mediated invasion and cytoskeletal rearrangements. Mol Microbiol 31:859–870. doi: 10.1046/j.1365-2958.1999.01223.x [DOI] [PubMed] [Google Scholar]
101. Molinari G, Talay SR, Valentin-Weigand P, Rohde M, Chhatwal GS. 1997. The fibronectin-binding protein of Streptococcus pyogenes, SfbI, is involved in the internalization of group A streptococci by epithelial cells. Infect Immun 65:1357–1363. doi: 10.1128/iai.65.4.1357-1363.1997 [DOI] [PMC free article] [PubMed] [Google Scholar]
102. Ozeri V, Rosenshine I, Mosher DF, Fässler R, Hanski E. 1998. Roles of integrins and fibronectin in the entry of Streptococcus pyogenes into cells via protein F1. Mol Microbiol 30:625–637. doi: 10.1046/j.1365-2958.1998.01097.x [DOI] [PubMed] [Google Scholar]
103. Rezcallah MS, Hodges K, Gill DB, Atkinson JP, Wang B, Cleary PP. 2005. Engagement of CD46 and α5β1 integrin by group A streptococci is required for efficient invasion of epithelial cells. Cell Microbiol 7:645–653. doi: 10.1111/j.1462-5822.2004.00497.x [DOI] [PubMed] [Google Scholar]
104. Catton EA, Bonsor DA, Herrera C, Stålhammar-Carlemalm M, Lyndin M, Turner CE, Soden J, van Strijp JAG, Singer BB, van Sorge NM, Lindahl G, McCarthy AJ. 2023. Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis. Nat Commun 14:2675. doi: 10.1038/s41467-023-38372-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
105. Hall A. 1998. Rho GTPases and the actin cytoskeleton. Science 279:509–514. doi: 10.1126/science.279.5350.509 [DOI] [PubMed] [Google Scholar]
106. Mishima W, Suzuki A, Yamaji S, Yoshimi R, Ueda A, Kaneko T, Tanaka J, Miwa Y, Ohno S, Ishigatsubo Y. 2004. The first CH domain of affixin activates Cdc42 and Rac1 through αPIX, a Cdc42/Rac1-specific guanine nucleotide exchanging factor. Genes Cells 9:193–204. doi: 10.1111/j.1356-9597.2004.00717.x [DOI] [PubMed] [Google Scholar]
107. Moss J, Vaughan M. 1988. ADP-ribosylation of guanyl nucleotide-binding regulatory proteins by bacterial toxins. Adv Enzymol Relat Areas Mol Biol 61:303–379. doi: 10.1002/9780470123072.ch6 [DOI] [PubMed] [Google Scholar]
108. Nerlich A, Rohde M, Talay SR, Genth H, Just I, Chhatwal GS. 2009. Invasion of endothelial cells by tissue-invasive M3 type group A streptococci requires Src kinase and activation of Rac1 by a phosphatidylinositol 3-kinase-independent mechanism. J Biol Chem 284:20319–20328. doi: 10.1074/jbc.M109.016501 [DOI] [PMC free article] [PubMed] [Google Scholar]
109. Ozeri V, Rosenshine I, Ben-Ze’Ev A, Bokoch GM, Jou TS, Hanski E. 2001. De novo formation of focal complex-like structures in host cells by invading streptococci. Mol Microbiol 41:561–573. doi: 10.1046/j.1365-2958.2001.02535.x [DOI] [PubMed] [Google Scholar]
110. Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S. 1996. Regulation of cell adhesion and anchorage-dependent growth by a new β1-integrin-linked protein kinase. Nature 379:91–96. doi: 10.1038/379091a0 [DOI] [PubMed] [Google Scholar]
111. Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D, Yan J, Sanghera J, Walsh MP, Dedhar S. 2001. Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. J Biol Chem 276:27462–27469. doi: 10.1074/jbc.M102940200 [DOI] [PubMed] [Google Scholar]
112. Purushothaman SS, Wang B, Cleary PP. 2003. M1 protein triggers a phosphoinositide cascade for group A Streptococcus invasion of epithelial cells. Infect Immun 71:5823–5830. doi: 10.1128/IAI.71.10.5823-5830.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
113. Nikolopoulos SN, Turner CE. 2001. Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions. J Biol Chem 276:23499–23505. doi: 10.1074/jbc.M102163200 [DOI] [PubMed] [Google Scholar]
114. Wang B, Li S, Dedhar S, Cleary PP. 2007. Paxillin phosphorylation: bifurcation point downstream of integrin-linked kinase (ILK) in streptococcal invasion. Cell Microbiol 9:1519–1528. doi: 10.1111/j.1462-5822.2007.00889.x [DOI] [PubMed] [Google Scholar]
115. Kasper KJ, Zeppa JJ, Wakabayashi AT, Xu SX, Mazzuca DM, Welch I, Baroja ML, Kotb M, Cairns E, Cleary PP, Haeryfar SMM, McCormick JK. 2014. Bacterial superantigens promote acute nasopharyngeal infection by Streptococcus pyogenes in a human MHC class II-dependent manner. PLoS Pathog 10:e1004155. doi: 10.1371/journal.ppat.1004155 [DOI] [PMC free article] [PubMed] [Google Scholar]
116. Klenk M, Koczan D, Guthke R, Nakata M, Thiesen HJ, Podbielski A, Kreikemeyer B. 2005. Global epithelial cell transcriptional responses reveal Streptococcus pyogenes Fas regulator activity association with bacterial aggressiveness. Cell Microbiol 7:1237–1250. doi: 10.1111/j.1462-5822.2005.00548.x [DOI] [PubMed] [Google Scholar]
117. Soderholm AT, Barnett TC, Sweet MJ, Walker MJ. 2018. Group A streptococcal pharyngitis: immune responses involved in bacterial clearance and GAS-associated immunopathologies. J Leukoc Biol 103:193–213. doi: 10.1189/jlb.4MR0617-227RR [DOI] [PubMed] [Google Scholar]
118. Tsai PJ, Chen YH, Hsueh CH, Hsieh HC, Liu YH, Wu JJ, Tsou CC. 2006. Streptococcus pyogenes induces epithelial inflammatory responses through NF-κB/MAPK signaling pathways. Microbes Infect 8:1440–1449. doi: 10.1016/j.micinf.2006.01.002 [DOI] [PubMed] [Google Scholar]
119. Wang B, Dileepan T, Briscoe S, Hyland KA, Kang J, Khoruts A, Cleary PP. 2010. Induction of TGF-β1 and TGF-β1-dependent predominant Th17 differentiation by group A streptococcal infection. Proc Natl Acad Sci U S A 107:5937–5942. doi: 10.1073/pnas.0904831107 [DOI] [PMC free article] [PubMed] [Google Scholar]
120. Gaffen SL, Jain R, Garg AV, Cua DJ. 2014. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 14:585–600. doi: 10.1038/nri3707 [DOI] [PMC free article] [PubMed] [Google Scholar]
121. Gordon S. 2016. Phagocytosis: an immunobiologic process. Immunity 44:463–475. doi: 10.1016/j.immuni.2016.02.026 [DOI] [PubMed] [Google Scholar]
122. Rabinovitch M. 1995. Professional and non-professional phagocytes: an introduction. Trends Cell Biol 5:85–87. doi: 10.1016/s0962-8924(00)88955-2 [DOI] [PubMed] [Google Scholar]
123. Zhu H, Liu M, Sumby P, Lei B. 2009. The secreted esterase of group A Streptococcus is important for invasive skin infection and dissemination in mice. Infect Immun 77:5225–5232. doi: 10.1128/IAI.00636-09 [DOI] [PMC free article] [PubMed] [Google Scholar]
124. Liu M, Zhu H, Li J, Garcia CC, Feng W, Kirpotina LN, Hilmer J, Tavares LP, Layton AW, Quinn MT, Bothner B, Teixeira MM, Lei B. 2012. Group A Streptococcus secreted esterase hydrolyzes platelet-activating factor to impede neutrophil recruitment and facilitate innate immune evasion. PLoS Pathog 8:e1002624. doi: 10.1371/journal.ppat.1002624 [DOI] [PMC free article] [PubMed] [Google Scholar]
125. Edwards RJ, Taylor GW, Ferguson M, Murray S, Rendell N, Wrigley A, Bai Z, Boyle J, Finney SJ, Jones A, Russell HH, Turner C, Cohen J, Faulkner L, Sriskandan S. 2005. Specific C-terminal cleavage and inactivation of interleukin-8 by invasive disease isolates of Streptococcus pyogenes. J Infect Dis 192:783–790. doi: 10.1086/432485 [DOI] [PubMed] [Google Scholar]
126. Middleton J, Neil S, Wintle J, Clark-Lewis I, Moore H, Lam C, Auer M, Hub E, Rot A. 1997. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91:385–395. doi: 10.1016/s0092-8674(00)80422-5 [DOI] [PubMed] [Google Scholar]
127. Zinkernagel AS, Timmer AM, Pence MA, Locke JB, Buchanan JT, Turner CE, Mishalian I, Sriskandan S, Hanski E, Nizet V. 2008. The IL-8 protease SpyCEP/ScpC of group A Streptococcus promotes resistance to neutrophil killing. Cell Host Microbe 4:170–178. doi: 10.1016/j.chom.2008.07.002 [DOI] [PMC free article] [PubMed] [Google Scholar]
128. Nozawa T, Iibushi J, Toh H, Minowa-Nozawa A, Murase K, Aikawa C, Nakagawa I. 2021. Intracellular group A Streptococcus induces Golgi fragmentation to impair host defenses through streptolysin O and NAD-glycohydrolase. mBio 12:e01974-20. doi: 10.1128/mBio.01974-20 [DOI] [PMC free article] [PubMed] [Google Scholar]
129. Imai T, Matsumura T, Mayer-Lambertz S, Wells CA, Ishikawa E, Butcher SK, Barnett TC, Walker MJ, Imamura A, Ishida H, Ikebe T, Miyamoto T, Ato M, Ohga S, Lepenies B, van Sorge NM, Yamasaki S. 2018. Lipoteichoic acid anchor triggers mincle to drive protective immunity against invasive group A Streptococcus infection. Proc Natl Acad Sci U S A 115:E10662–E10671. doi: 10.1073/pnas.1809100115 [DOI] [PMC free article] [PubMed] [Google Scholar]
130. Moses AE, Wessels MR, Zalcman K, Albertí S, Natanson-Yaron S, Menes T, Hanski E. 1997. Relative contributions of hyaluronic acid capsule and M protein to virulence in a mucoid strain of the group A Streptococcus. Infect Immun 65:64–71. doi: 10.1128/iai.65.1.64-71.1997 [DOI] [PMC free article] [PubMed] [Google Scholar]
131. Spencer RC. 1995. Invasive streptococci. Eur J Clin Microbiol Infect Dis 14:S26–S32. [PubMed] [Google Scholar]
132. Dinkla K, Rohde M, Jansen WTM, Carapetis JR, Chhatwal GS, Talay SR. 2003. Streptococcus pyogenes recruits collagen via surface-bound fibronectin: a novel colonization and immune evasion mechanism. Mol Microbiol 47:861–869. doi: 10.1046/j.1365-2958.2003.03352.x [DOI] [PubMed] [Google Scholar]
133. Lembke C, Podbielski A, Hidalgo-Grass C, Jonas L, Hanski E, Kreikemeyer B. 2006. Characterization of biofilm formation by clinically relevant serotypes of group A streptococci. Appl Environ Microbiol 72:2864–2875. doi: 10.1128/AEM.72.4.2864-2875.2006 [DOI] [PMC free article] [PubMed] [Google Scholar]
134. Underhill DM, Goodridge HS. 2012. Information processing during phagocytosis. Nat Rev Immunol 12:492–502. doi: 10.1038/nri3244 [DOI] [PMC free article] [PubMed] [Google Scholar]
135. Sandin C, Carlsson F, Lindahl G. 2006. Binding of human plasma proteins to Streptococcus pyogenes M protein determines the location of opsonic and non-opsonic epitopes. Mol Microbiol 59:20–30. doi: 10.1111/j.1365-2958.2005.04913.x [DOI] [PubMed] [Google Scholar]
136. Hoe NP, Ireland RM, DeLeo FR, Gowen BB, Dorward DW, Voyich JM, Liu M, Burns EH, Culnan DM, Bretscher A, Musser JM. 2002. Insight into the molecular basis of pathogen abundance: group A Streptococcus inhibitor of complement inhibits bacterial adherence and internalization into human cells. Proc Natl Acad Sci U S A 99:7646–7651. doi: 10.1073/pnas.112039899 [DOI] [PMC free article] [PubMed] [Google Scholar]
137. Coye LH, Collins CM. 2004. Identification of SpyA, a novel ADP-ribosyltransferase of Streptococcus pyogenes. Mol Microbiol 54:89–98. doi: 10.1111/j.1365-2958.2004.04262.x [DOI] [PubMed] [Google Scholar]
138. Hoff JS, DeWald M, Moseley SL, Collins CM, Voyich JM. 2011. SpyA, a C3-like ADP-ribosyltransferase, contributes to virulence in a mouse subcutaneous model of Streptococcus pyogenes infection. Infect Immun 79:2404–2411. doi: 10.1128/IAI.01191-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
139. Korotkova N, Hoff JS, Becker DM, Quinn JKH, Icenogle LM, Moseley SL. 2012. SpyA is a membrane-bound ADP-ribosyltransferase of Streptococcus pyogenes which modifies a streptococcal peptide, SpyB. Mol Microbiol 83:936–952. doi: 10.1111/j.1365-2958.2012.07979.x [DOI] [PMC free article] [PubMed] [Google Scholar]
140. Datta V, Myskowski SM, Kwinn LA, Chiem DN, Varki N, Kansal RG, Kotb M, Nizet V. 2005. Mutational analysis of the group A streptococcal operon encoding streptolysin S and its virulence role in invasive infection. Mol Microbiol 56:681–695. doi: 10.1111/j.1365-2958.2005.04583.x [DOI] [PubMed] [Google Scholar]
141. Feil SC, Ascher DB, Kuiper MJ, Tweten RK, Parker MW. 2014. Structural studies of Streptococcus pyogenes streptolysin O provide insights into the early steps of membrane penetration. J Mol Biol 426:785–792. doi: 10.1016/j.jmb.2013.11.020 [DOI] [PMC free article] [PubMed] [Google Scholar]
142. Sierig G, Cywes C, Wessels MR, Ashbaugh CD. 2003. Cytotoxic effects of streptolysin O and streptolysin S enhance the virulence of poorly encapsulated group A streptococci. Infect Immun 71:446–455. doi: 10.1128/IAI.71.1.446-455.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
143. Herwald H, Cramer H, Mörgelin M, Russell W, Sollenberg U, Norrby-Teglund A, Flodgaard H, Lindbom L, Björck L. 2004. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell 116:367–379. doi: 10.1016/s0092-8674(04)00057-1 [DOI] [PubMed] [Google Scholar]
144. Macheboeuf P, Buffalo C, Fu CY, Zinkernagel AS, Cole JN, Johnson JE, Nizet V, Ghosh P. 2011. Streptococcal M1 protein constructs a pathological host fibrinogen network. Nature 472:64–68. doi: 10.1038/nature09967 [DOI] [PMC free article] [PubMed] [Google Scholar]
145. Håkansson A, Bentley CC, Shakhnovic EA, Wessels MR. 2005. Cytolysin-dependent evasion of lysosomal killing. Proc Natl Acad Sci U S A 102:5192–5197. doi: 10.1073/pnas.0408721102 [DOI] [PMC free article] [PubMed] [Google Scholar]
146. Michos A, Gryllos I, Håkansson A, Srivastava A, Kokkotou E, Wessels MR. 2006. Enhancement of streptolysin O activity and intrinsic cytotoxic effects of the group A streptococcal toxin, NAD-glycohydrolase. J Biol Chem 281:8216–8223. doi: 10.1074/jbc.M511674200 [DOI] [PubMed] [Google Scholar]
147. Harder J, Franchi L, Muñoz-Planillo R, Park JH, Reimer T, Núñez G. 2009. Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-κB activation but proceeds independently of TLR signaling and P2X7 receptor. J Immunol 183:5823–5829. doi: 10.4049/jimmunol.0900444 [DOI] [PMC free article] [PubMed] [Google Scholar]
148. Keyel PA, Roth R, Yokoyama WM, Heuser JE, Salter RD. 2013. Reduction of streptolysin O (SLO) pore-forming activity enhances inflammasome activation. Toxins (Basel) 5:1105–1118. doi: 10.3390/toxins5061105 [DOI] [PMC free article] [PubMed] [Google Scholar]
149. Lin AE, Beasley FC, Keller N, Hollands A, Urbano R, Troemel ER, Hoffman HM, Nizet V. 2015. A group A Streptococcus ADP-ribosyltransferase toxin stimulates a protective interleukin 1β-dependent macrophage immune response. mBio 6:e00133. doi: 10.1128/mBio.00133-15 [DOI] [PMC free article] [PubMed] [Google Scholar]
150. Deng W, Bai Y, Deng F, Pan Y, Mei S, Zheng Z, Min R, Wu Z, Li W, Miao R, Zhang Z, Kupper TS, Lieberman J, Liu X. 2022. Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis. Nature 608:496–502. doi: 10.1038/s41586-022-05109-x [DOI] [PMC free article] [PubMed] [Google Scholar]
151. LaRock DL, Johnson AF, Wilde S, Sands JS, Monteiro MP, LaRock CN. 2022. Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes. Nature 605:527–531. doi: 10.1038/s41586-022-04717-x [DOI] [PMC free article] [PubMed] [Google Scholar]
152. Muñoz-Planillo R, Kuffa P, Martínez-Colón G, Smith BL, Rajendiran TM, Núñez G. 2013. K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38:1142–1153. doi: 10.1016/j.immuni.2013.05.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
153. Valderrama JA, Riestra AM, Gao NJ, LaRock CN, Gupta N, Ali SR, Hoffman HM, Ghosh P, Nizet V. 2017. Group A streptococcal M protein activates the NLRP3 inflammasome. Nat Microbiol 2:1425–1434. doi: 10.1038/s41564-017-0005-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
154. Timmer AM, Timmer JC, Pence MA, Hsu LC, Ghochani M, Frey TG, Karin M, Salvesen GS, Nizet V. 2009. Streptolysin O promotes group A Streptococcus immune evasion by accelerated macrophage apoptosis. J Biol Chem 284:862–871. doi: 10.1074/jbc.M804632200 [DOI] [PMC free article] [PubMed] [Google Scholar]
155. Tamura F, Nakagawa R, Akuta T, Okamoto S, Hamada S, Maeda H, Kawabata S, Akaike T. 2004. Proapoptotic effect of proteolytic activation of matrix metalloproteinases by Streptococcus pyogenes thiol proteinase (Streptococcus pyrogenic exotoxin B). Infect Immun 72:4836–4847. doi: 10.1128/IAI.72.8.4836-4847.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
156. Chiang-Ni C, Wang CH, Tsai PJ, Chuang WJ, Lin YS, Lin MT, Liu CC, Wu JJ. 2006. Streptococcal pyrogenic exotoxin B causes mitochondria damage to polymorphonuclear cells preventing phagocytosis of group A Streptococcus. Med Microbiol Immunol 195:55–63. doi: 10.1007/s00430-005-0001-y [DOI] [PubMed] [Google Scholar]
157. Kuo CF, Wu JJ, Tsai PJ, Kao FJ, Lei HY, Lin MT, Lin YS. 1999. Streptococcal pyrogenic exotoxin B induces apoptosis and reduces phagocytic activity in U937 cells. Infect Immun 67:126–130. doi: 10.1128/IAI.67.1.126-130.1999 [DOI] [PMC free article] [PubMed] [Google Scholar]
158. Nakagawa I, Nakata M, Kawabata S, Hamada S. 2004. Transcriptome analysis and gene expression profiles of early apoptosis-related genes in Streptococcus pyogenes-infected epithelial cells. Cell Microbiol 6:939–952. doi: 10.1111/j.1462-5822.2004.00412.x [DOI] [PubMed] [Google Scholar]
159. Tsai PJ, Kuo CF, Lin KY, Lin YS, Lei HY, Chen FF, Wang JR, Wu JJ. 1998. Effect of group A streptococcal cysteine protease on invasion of epithelial cells. Infect Immun 66:1460–1466. doi: 10.1128/IAI.66.4.1460-1466.1998 [DOI] [PMC free article] [PubMed] [Google Scholar]
160. Tsai PJ, Lin YS, Kuo CF, Lei HY, Wu JJ. 1999. Group A Streptococcus induces apoptosis in human epithelial cells. Infect Immun 67:4334–4339. doi: 10.1128/IAI.67.9.4334-4339.1999 [DOI] [PMC free article] [PubMed] [Google Scholar]
161. Brozna JP, Hauff NF, Phillips WA, Johnston Jr RB. 1988. Activation of the respiratory burst in macrophages. Phosphorylation specifically associated with Fc receptor-mediated stimulation. J Immunol 141:1642–1647. doi: 10.4049/jimmunol.141.5.1642 [DOI] [PubMed] [Google Scholar]
162. Dahlgren C, Karlsson A. 1999. Respiratory burst in human neutrophils. J Immunol Methods 232:3–14. doi: 10.1016/s0022-1759(99)00146-5 [DOI] [PubMed] [Google Scholar]
163. Nauseef WM. 2004. Assembly of the phagocyte NADPH oxidase. Histochem Cell Biol 122:277–291. doi: 10.1007/s00418-004-0679-8 [DOI] [PubMed] [Google Scholar]
164. Winterbourn CC. 2002. Biological reactivity and biomarkers of the neutrophil oxidant, hypochlorous acid. Toxicology 181–182:223–227. doi: 10.1016/s0300-483x(02)00286-x [DOI] [PubMed] [Google Scholar]
165. Glaeser J, Nuss AM, Berghoff BA, Klug G. 2011. Singlet oxygen stress in microorganisms. Adv Microb Physiol 58:141–173. doi: 10.1016/B978-0-12-381043-4.00004-0 [DOI] [PubMed] [Google Scholar]
166. Henningham A, Döhrmann S, Nizet V, Cole JN. 2015. Mechanisms of group A Streptococcus resistance to reactive oxygen species. FEMS Microbiol Rev 39:488–508. doi: 10.1093/femsre/fuu009 [DOI] [PMC free article] [PubMed] [Google Scholar]
167. Cleary PP, Larkin A. 1979. Hyaluronic acid capsule: strategy for oxygen resistance in group A streptococci. J Bacteriol 140:1090–1097. doi: 10.1128/jb.140.3.1090-1097.1979 [DOI] [PMC free article] [PubMed] [Google Scholar]
168. Söderberg JJ, Engström P, von Pawel-Rammingen U. 2008. The intrinsic immunoglobulin G endopeptidase activity of streptococcal Mac-2 proteins implies a unique role for the enzymatically impaired Mac-2 protein of M28 serotype strains. Infect Immun 76:2183–2188. doi: 10.1128/IAI.01422-07 [DOI] [PMC free article] [PubMed] [Google Scholar]
169. Staali L, Bauer S, Mörgelin M, Björck L, Tapper H. 2006. Streptococcus pyogenes bacteria modulate membrane traffic in human neutrophils and selectively inhibit azurophilic granule fusion with phagosomes. Cell Microbiol 8:690–703. doi: 10.1111/j.1462-5822.2005.00662.x [DOI] [PubMed] [Google Scholar]
170. Brenot A, King KY, Caparon MG. 2005. The PerR regulon in peroxide resistance and virulence of Streptococcus pyogenes. Mol Microbiol 55:221–234. doi: 10.1111/j.1365-2958.2004.04370.x [DOI] [PubMed] [Google Scholar]
171. Brenot A, King KY, Janowiak B, Griffith O, Caparon MG. 2004. Contribution of glutathione peroxidase to the virulence of Streptococcus pyogenes. Infect Immun 72:408–413. doi: 10.1128/IAI.72.1.408-413.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
172. Gao H, Tiwari MK, Kang YC, Lee JK. 2012. Characterization of H₂O-forming NADH oxidase from Streptococcus pyogenes and its application in L-rare sugar production. Bioorg Med Chem Lett 22:1931–1935. doi: 10.1016/j.bmcl.2012.01.049 [DOI] [PubMed] [Google Scholar]
173. Gibson CM, Caparon MG. 1996. Insertional inactivation of Streptococcus pyogenes sod suggests that prtF is regulated in response to a superoxide signal. J Bacteriol 178:4688–4695. doi: 10.1128/jb.178.15.4688-4695.1996 [DOI] [PMC free article] [PubMed] [Google Scholar]
174. King KY, Horenstein JA, Caparon MG. 2000. Aerotolerance and peroxide resistance in peroxidase and PerR mutants of Streptococcus pyogenes. J Bacteriol 182:5290–5299. doi: 10.1128/JB.182.19.5290-5299.2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
175. Gibson CM, Mallett TC, Claiborne A, Caparon MG. 2000. Contribution of NADH oxidase to aerobic metabolism of Streptococcus pyogenes. J Bacteriol 182:448–455. doi: 10.1128/JB.182.2.448-455.2000 [DOI] [PMC free article] [PubMed] [Google Scholar]
176. Rosch JW, Caparon MG. 2005. The ExPortal: an organelle dedicated to the biogenesis of secreted proteins in Streptococcus pyogenes. Mol Microbiol 58:959–968. doi: 10.1111/j.1365-2958.2005.04887.x [DOI] [PubMed] [Google Scholar]
177. Toukoki C, Gryllos I. 2013. PolA1, a putative DNA polymerase I, is coexpressed with PerR and contributes to peroxide stress defenses of group A Streptococcus. J Bacteriol 195:717–725. doi: 10.1128/JB.01847-12 [DOI] [PMC free article] [PubMed] [Google Scholar]
178. Bates CS, Montañez GE, Woods CR, Vincent RM, Eichenbaum Z. 2003. Identification and characterization of a Streptococcus pyogenes operon involved in binding of hemoproteins and acquisition of iron. Infect Immun 71:1042–1055. doi: 10.1128/IAI.71.3.1042-1055.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
179. Brenot A, Weston BF, Caparon MG. 2007. A PerR-regulated metal transporter (PmtA) is an interface between oxidative stress and metal homeostasis in Streptococcus pyogenes. Mol Microbiol 63:1185–1196. doi: 10.1111/j.1365-2958.2006.05577.x [DOI] [PubMed] [Google Scholar]
180. Gryllos I, Grifantini R, Colaprico A, Cary ME, Hakansson A, Carey DW, Suarez-Chavez M, Kalish LA, Mitchell PD, White GL, Wessels MR. 2008. PerR confers phagocytic killing resistance and allows pharyngeal colonization by group A Streptococcus. PLoS Pathog 4:e1000145. doi: 10.1371/journal.ppat.1000145 [DOI] [PMC free article] [PubMed] [Google Scholar]
181. Janulczyk R, Ricci S, Björck L. 2003. MtsABC is important for manganese and iron transport, oxidative stress resistance, and virulence of Streptococcus pyogenes. Infect Immun 71:2656–2664. doi: 10.1128/IAI.71.5.2656-2664.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
182. Tsou CC, Chiang-Ni C, Lin YS, Chuang WJ, Lin MT, Liu CC, Wu JJ. 2008. An iron-binding protein, Dpr, decreases hydrogen peroxide stress and protects Streptococcus pyogenes against multiple stresses. Infect Immun 76:4038–4045. doi: 10.1128/IAI.00477-08 [DOI] [PMC free article] [PubMed] [Google Scholar]
183. Tsou CC, Chiang-Ni C, Lin YS, Chuang WJ, Lin MT, Liu CC, Wu JJ. 2010. Oxidative stress and metal ions regulate a ferritin-like gene, Dpr, in Streptococcus pyogenes. Int J Med Microbiol 300:259–264. doi: 10.1016/j.ijmm.2009.09.002 [DOI] [PubMed] [Google Scholar]
184. Bates CS, Toukoki C, Neely MN, Eichenbaum Z. 2005. Characterization of MtsR, a new metal regulator in group A Streptococcus, involved in iron acquisition and virulence. Infect Immun 73:5743–5753. doi: 10.1128/IAI.73.9.5743-5753.2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
185. Chaussee MA, Callegari EA, Chaussee MS. 2004. Rgg regulates growth phase-dependent expression of proteins associated with secondary metabolism and stress in Streptococcus pyogenes. J Bacteriol 186:7091–7099. doi: 10.1128/JB.186.21.7091-7099.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
186. Riani C, Standar K, Srimuang S, Lembke C, Kreikemeyer B, Podbielski A. 2007. Transcriptome analyses extend understanding of Streptococcus pyogenes regulatory mechanisms and behavior toward immunomodulatory substances. Int J Med Microbiol 297:513–523. doi: 10.1016/j.ijmm.2007.04.005 [DOI] [PubMed] [Google Scholar]
187. Ricci S, Janulczyk R, Björck L. 2002. The regulator PerR is involved in oxidative stress response and iron homeostasis and is necessary for full virulence of Streptococcus pyogenes. Infect Immun 70:4968–4976. doi: 10.1128/IAI.70.9.4968-4976.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]
188. Voyich JM, Braughton KR, Sturdevant DE, Vuong C, Kobayashi SD, Porcella SF, Otto M, Musser JM, DeLeo FR. 2004. Engagement of the pathogen survival response used by group A Streptococcus to avert destruction by innate host defense. J Immunol 173:1194–1201. doi: 10.4049/jimmunol.173.2.1194 [DOI] [PubMed] [Google Scholar]
189. Voyich JM, Sturdevant DE, Braughton KR, Kobayashi SD, Lei B, Virtaneva K, Dorward DW, Musser JM, DeLeo FR. 2003. Genome-wide protective response used by group A Streptococcus to evade destruction by human polymorphonuclear leukocytes. Proc Natl Acad Sci U S A 100:1996–2001. doi: 10.1073/pnas.0337370100 [DOI] [PMC free article] [PubMed] [Google Scholar]
190. Döhrmann S, Anik S, Olson J, Anderson EL, Etesami N, No H, Snipper J, Nizet V, Okumura CYM. 2014. Role for streptococcal collagen-like protein 1 in M1T1 group A Streptococcus resistance to neutrophil extracellular traps. Infect Immun 82:4011–4020. doi: 10.1128/IAI.01921-14 [DOI] [PMC free article] [PubMed] [Google Scholar]
191. Harlan JM, Levine JD, Callahan KS, Schwartz BR, Harker LA. 1984. Glutathione redox cycle protects cultured endothelial cells against lysis by extracellularly generated hydrogen peroxide. J Clin Invest 73:706–713. doi: 10.1172/JCI111263 [DOI] [PMC free article] [PubMed] [Google Scholar]
192. Brouwer S, Jespersen MG, Ong CLY, De Oliveira DMP, Keller B, Cork AJ, Djoko KY, Davies MR, Walker MJ. 2022. Streptococcus pyogenes hijacks host glutathione for growth and innate immune evasion. mBio 13:e0067622. doi: 10.1128/mbio.00676-22 [DOI] [PMC free article] [PubMed] [Google Scholar]
193. Cederlund A, Gudmundsson GH, Agerberth B. 2011. Antimicrobial peptides important in innate immunity. FEBS J 278:3942–3951. doi: 10.1111/j.1742-4658.2011.08302.x [DOI] [PubMed] [Google Scholar]
194. Ganz T. 2004. Antimicrobial polypeptides. J Leukoc Biol 75:34–38. doi: 10.1189/jlb.0403150 [DOI] [PubMed] [Google Scholar]
195. Kristian SA, Datta V, Weidenmaier C, Kansal R, Fedtke I, Peschel A, Gallo RL, Nizet V. 2005. D-alanylation of teichoic acids promotes group A Streptococcus antimicrobial peptide resistance, neutrophil survival, and epithelial cell invasion. J Bacteriol 187:6719–6725. doi: 10.1128/JB.187.19.6719-6725.2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
196. Cole JN, Pence MA, von Köckritz-Blickwede M, Hollands A, Gallo RL, Walker MJ, Nizet V. 2010. M protein and hyaluronic acid capsule are essential for in vivo selection of covRS mutations characteristic of invasive serotype M1T1 group A Streptococcus. mBio 1:e00191-10. doi: 10.1128/mBio.00191-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
197. LaRock CN, Döhrmann S, Todd J, Corriden R, Olson J, Johannssen T, Lepenies B, Gallo RL, Ghosh P, Nizet V. 2015. Group A streptococcal M1 protein sequesters cathelicidin to evade innate immune killing. Cell Host Microbe 18:471–477. doi: 10.1016/j.chom.2015.09.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
198. Lauth X, von Köckritz-Blickwede M, McNamara CW, Myskowski S, Zinkernagel AS, Beall B, Ghosh P, Gallo RL, Nizet V. 2009. M1 protein allows group A streptococcal survival in phagocyte extracellular traps through cathelicidin inhibition. J Innate Immun 1:202–214. doi: 10.1159/000203645 [DOI] [PMC free article] [PubMed] [Google Scholar]
199. Pence MA, Rooijakkers SHM, Cogen AL, Cole JN, Hollands A, Gallo RL, Nizet V. 2010. Streptococcal inhibitor of complement promotes innate immune resistance phenotypes of invasive M1T1 group A Streptococcus. J Innate Immun 2:587–595. doi: 10.1159/000317672 [DOI] [PMC free article] [PubMed] [Google Scholar]
200. Hollands A, Gonzalez D, Leire E, Donald C, Gallo RL, Sanderson-Smith M, Dorrestein PC, Nizet V. 2012. A bacterial pathogen co-opts host plasmin to resist killing by cathelicidin antimicrobial peptides. J Biol Chem 287:40891–40897. doi: 10.1074/jbc.M112.404582 [DOI] [PMC free article] [PubMed] [Google Scholar]
201. Johansson L, Thulin P, Sendi P, Hertzén E, Linder A, Akesson P, Low DE, Agerberth B, Norrby-Teglund A. 2008. Cathelicidin LL-37 in severe Streptococcus pyogenes soft tissue infections in humans. Infect Immun 76:3399–3404. doi: 10.1128/IAI.01392-07 [DOI] [PMC free article] [PubMed] [Google Scholar]
202. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. 2004. Neutrophil extracellular traps kill bacteria. Science 303:1532–1535. doi: 10.1126/science.1092385 [DOI] [PubMed] [Google Scholar]
203. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y, Brinkmann V, Zychlinsky A. 2007. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176:231–241. doi: 10.1083/jcb.200606027 [DOI] [PMC free article] [PubMed] [Google Scholar]
204. Khan MA, Palaniyar N. 2017. Transcriptional firing helps to drive NETosis. Sci Rep 7:41749. doi: 10.1038/srep41749 [DOI] [PMC free article] [PubMed] [Google Scholar]
205. Steinberg BE, Grinstein S. 2007. Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death. Sci STKE 2007:e11. doi: 10.1126/stke.3792007pe11 [DOI] [PubMed] [Google Scholar]
206. Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, Feramisco J, Nizet V. 2006. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 16:396–400. doi: 10.1016/j.cub.2005.12.039 [DOI] [PubMed] [Google Scholar]
207. Döhrmann S, LaRock CN, Anderson EL, Cole JN, Ryali B, Stewart C, Nonejuie P, Pogliano J, Corriden R, Ghosh P, Nizet V. 2017. Group A streptococcal M1 protein provides resistance against the antimicrobial activity of histones. Sci Rep 7:43039. doi: 10.1038/srep43039 [DOI] [PMC free article] [PubMed] [Google Scholar]
208. Mayadas TN, Cullere X, Lowell CA. 2014. The multifaceted functions of neutrophils. Annu Rev Pathol 9:181–218. doi: 10.1146/annurev-pathol-020712-164023 [DOI] [PMC free article] [PubMed] [Google Scholar]
209. Pinheiro da Silva F, Machado MCC. 2012. Antimicrobial peptides: clinical relevance and therapeutic implications. Peptides 36:308–314. doi: 10.1016/j.peptides.2012.05.014 [DOI] [PubMed] [Google Scholar]
210. Winterbourn CC, Metodiewa D. 1999. Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide. Free Radic Biol Med 27:322–328. doi: 10.1016/s0891-5849(99)00051-9 [DOI] [PubMed] [Google Scholar]
211. Kimmey JM, Stallings CL. 2016. Bacterial pathogens versus autophagy: implications for therapeutic interventions. Trends Mol Med 22:1060–1076. doi: 10.1016/j.molmed.2016.10.008 [DOI] [PMC free article] [PubMed] [Google Scholar]
212. Siqueira MDS, Ribeiro RDM, Travassos LH. 2018. Autophagy and its interaction with intracellular bacterial pathogens. Front Immunol 9:935. doi: 10.3389/fimmu.2018.00935 [DOI] [PMC free article] [PubMed] [Google Scholar]
213. Zhao YG, Codogno P, Zhang H. 2021. Machinery, regulation and pathophysiological implications of autophagosome maturation. Nat Rev Mol Cell Biol 22:733–750. doi: 10.1038/s41580-021-00392-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
214. Zhao YG, Zhang H. 2019. Autophagosome maturation: an epic journey from the ER to lysosomes. J Cell Biol 218:757–770. doi: 10.1083/jcb.201810099 [DOI] [PMC free article] [PubMed] [Google Scholar]
215. Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S, Yoshimori T. 2004. Autophagy defends cells against invading group A Streptococcus. Science 306:1037–1040. doi: 10.1126/science.1103966 [DOI] [PubMed] [Google Scholar]
216. Yamaguchi H, Nakagawa I, Yamamoto A, Amano A, Noda T, Yoshimori T. 2009. An initial step of GAS-containing autophagosome-like vacuoles formation requires Rab7. PLoS Pathog 5:e1000670. doi: 10.1371/journal.ppat.1000670 [DOI] [PMC free article] [PubMed] [Google Scholar]
217. Nozawa T, Aikawa C, Goda A, Maruyama F, Hamada S, Nakagawa I. 2012. The small GTPases Rab9A and Rab23 function at distinct steps in autophagy during group A Streptococcus infection. Cell Microbiol 14:1149–1165. doi: 10.1111/j.1462-5822.2012.01792.x [DOI] [PubMed] [Google Scholar]
218. Sakurai A, Maruyama F, Funao J, Nozawa T, Aikawa C, Okahashi N, Shintani S, Hamada S, Ooshima T, Nakagawa I. 2010. Specific behavior of intracellular Streptococcus pyogenes that has undergone autophagic degradation is associated with bacterial streptolysin O and host small G proteins Rab5 and Rab7. J Biol Chem 285:22666–22675. doi: 10.1074/jbc.M109.100131 [DOI] [PMC free article] [PubMed] [Google Scholar]
219. Joubert PE, Meiffren G, Grégoire IP, Pontini G, Richetta C, Flacher M, Azocar O, Vidalain PO, Vidal M, Lotteau V, Codogno P, Rabourdin-Combe C, Faure M. 2009. Autophagy induction by the pathogen receptor CD46. Cell Host Microbe 6:354–366. doi: 10.1016/j.chom.2009.09.006 [DOI] [PubMed] [Google Scholar]
220. Wang J, Meng M, Li M, Guan X, Liu J, Gao X, Sun Q, Li J, Ma C, Wei L. 2020. Integrin α5β1, as a receptor of fibronectin, binds the FbaA protein of group A Streptococcus to initiate autophagy during infection. mBio 11:e00771-20. doi: 10.1128/mBio.00771-20 [DOI] [PMC free article] [PubMed] [Google Scholar]
221. Haobam B, Nozawa T, Minowa-Nozawa A, Tanaka M, Oda S, Watanabe T, Aikawa C, Maruyama F, Nakagawa I. 2014. Rab17-mediated recycling endosomes contribute to autophagosome formation in response to group A Streptococcus invasion. Cell Microbiol 16:1806–1821. doi: 10.1111/cmi.12329 [DOI] [PubMed] [Google Scholar]
222. Nozawa T, Aikawa C, Minowa-Nozawa A, Nakagawa I. 2017. The intracellular microbial sensor NLRP4 directs Rho-actin signaling to facilitate group A Streptococcus-containing autophagosome-like vacuole formation. Autophagy 13:1841–1854. doi: 10.1080/15548627.2017.1358343 [DOI] [PMC free article] [PubMed] [Google Scholar]
223. Nozawa T, Minowa-Nozawa A, Aikawa C, Nakagawa I. 2017. The STX6-VTI1B-VAMP3 complex facilitates xenophagy by regulating the fusion between recycling endosomes and autophagosomes. Autophagy 13:57–69. doi: 10.1080/15548627.2016.1241924 [DOI] [PMC free article] [PubMed] [Google Scholar]
224. Ito C, Saito Y, Nozawa T, Fujii S, Sawa T, Inoue H, Matsunaga T, Khan S, Akashi S, Hashimoto R, Aikawa C, Takahashi E, Sagara H, Komatsu M, Tanaka K, Akaike T, Nakagawa I, Arimoto H. 2013. Endogenous nitrated nucleotide is a key mediator of autophagy and innate defense against bacteria. Mol Cell 52:794–804. doi: 10.1016/j.molcel.2013.10.024 [DOI] [PubMed] [Google Scholar]
225. O’Seaghdha M, Wessels MR. 2013. Streptolysin O and its co-toxin NAD-glycohydrolase protect group A Streptococcus from Xenophagic killing. PLoS Pathog 9:e1003394. doi: 10.1371/journal.ppat.1003394 [DOI] [PMC free article] [PubMed] [Google Scholar]
226. Lin CY, Nozawa T, Minowa-Nozawa A, Toh H, Hikichi M, Iibushi J, Nakagawa I. 2020. Autophagy receptor Tollip facilitates bacterial autophagy by recruiting galectin-7 in response to group A Streptococcus infection. Front Cell Infect Microbiol 10:583137. doi: 10.3389/fcimb.2020.583137 [DOI] [PMC free article] [PubMed] [Google Scholar]
227. Nozawa T, Sano S, Minowa-Nozawa A, Toh H, Nakajima S, Murase K, Aikawa C, Nakagawa I. 2020. TBC1D9 regulates TBK1 activation through Ca²⁺ signaling in selective autophagy. Nat Commun 11:770. doi: 10.1038/s41467-020-14533-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
228. Hikichi M, Toh H, Minowa-Nozawa A, Nozawa T, Nakagawa I. 2022. Guanylate-binding protein 1 regulates infection-induced autophagy through TBK1 phosphorylation. Cell Microbiol 2022:1–18. doi: 10.1155/2022/8612113 [DOI] [Google Scholar]
229. Furuta N, Fujita N, Noda T, Yoshimori T, Amano A. 2010. Combinational soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins VAMP8 and Vti1B mediate fusion of antimicrobial and canonical autophagosomes with lysosomes. Mol Biol Cell 21:1001–1010. doi: 10.1091/mbc.e09-08-0693 [DOI] [PMC free article] [PubMed] [Google Scholar]
230. Wilkinson DS, Jariwala JS, Anderson E, Mitra K, Meisenhelder J, Chang JT, Ideker T, Hunter T, Nizet V, Dillin A, Hansen M. 2015. Phosphorylation of LC3 by the Hippo kinases STK3/STK4 is essential for autophagy. Mol Cell 57:55–68. doi: 10.1016/j.molcel.2014.11.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
231. Nakajima S, Aikawa C, Nozawa T, Minowa-Nozawa A, Toh H, Nakagawa I. 2017. Bcl-xL affects group A Streptococcus-induced autophagy directly, by inhibiting fusion between autophagosomes and lysosomes, and indirectly, by inhibiting bacterial internalization via interaction with Beclin 1-UVRAG. PLoS One 12:e0170138. doi: 10.1371/journal.pone.0170138 [DOI] [PMC free article] [PubMed] [Google Scholar]
232. Aikawa C, Nakajima S, Karimine M, Nozawa T, Minowa-Nozawa A, Toh H, Yamada S, Nakagawa I. 2018. NLRX1 negatively regulates group A Streptococcus invasion and autophagy induction by interacting with the Beclin 1-UVRAG complex. Front Cell Infect Microbiol 8:403. doi: 10.3389/fcimb.2018.00403 [DOI] [PMC free article] [PubMed] [Google Scholar]
233. Jounai N, Kobiyama K, Shiina M, Ogata K, Ishii KJ, Takeshita F. 2011. NLRP4 negatively regulates autophagic processes through an association with Beclin1. J Immunol 186:1646–1655. doi: 10.4049/jimmunol.1001654 [DOI] [PubMed] [Google Scholar]
234. Toh H, Nozawa T, Minowa-Nozawa A, Hikichi M, Nakajima S, Aikawa C, Nakagawa I. 2020. Group A Streptococcus modulates RAB1- and PIK3C3 complex-dependent autophagy. Autophagy 16:334–346. doi: 10.1080/15548627.2019.1628539 [DOI] [PMC free article] [PubMed] [Google Scholar]
235. Barnett TC, Liebl D, Seymour LM, Gillen CM, Lim JY, Larock CN, Davies MR, Schulz BL, Nizet V, Teasdale RD, Walker MJ. 2013. The globally disseminated M1T1 clone of group A Streptococcus evades autophagy for intracellular replication. Cell Host Microbe 14:675–682. doi: 10.1016/j.chom.2013.11.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
236. Bastiat-Sempe B, Love JF, Lomayesva N, Wessels MR. 2014. Streptolysin O and NAD-glycohydrolase prevent phagolysosome acidification and promote group A Streptococcus survival in macrophages. mBio 5:e01690-14. doi: 10.1128/mBio.01690-14 [DOI] [PMC free article] [PubMed] [Google Scholar]
237. O’Neill AM, Thurston TLM, Holden DW. 2016. Cytosolic replication of group A Streptococcus in human macrophages. mBio 7:e00931-16. doi: 10.1128/mBio.00931-16 [DOI] [PMC free article] [PubMed] [Google Scholar]
238. Sharma O, O’Seaghdha M, Velarde JJ, Wessels MR. 2016. NAD⁺-glycohydrolase promotes intracellular survival of group A Streptococcus. PLoS Pathog 12:e1005468. doi: 10.1371/journal.ppat.1005468 [DOI] [PMC free article] [PubMed] [Google Scholar]
239. Lu SL, Kuo CF, Chen HW, Yang YS, Liu CC, Anderson R, Wu JJ, Lin YS. 2015. Insufficient acidification of autophagosomes facilitates group A Streptococcus survival and growth in endothelial cells. mBio 6:e01435-15. doi: 10.1128/mBio.01435-15 [DOI] [PMC free article] [PubMed] [Google Scholar]
240. Lu SL, Kawabata T, Cheng YL, Omori H, Hamasaki M, Kusaba T, Iwamoto R, Arimoto H, Noda T, Lin YS, Yoshimori T. 2017. Endothelial cells are intrinsically defective in xenophagy of Streptococcus pyogenes. PLoS Pathog 13:e1006444. doi: 10.1371/journal.ppat.1006444 [DOI] [PMC free article] [PubMed] [Google Scholar]
241. Cheng YL, Wu YW, Kuo CF, Lu SL, Liu FT, Anderson R, Lin CF, Liu YL, Wang WY, Chen YD, Zheng PX, Wu JJ, Lin YS. 2017. Galectin-3 inhibits galectin-8/Parkin-mediated ubiquitination of group A Streptococcus. mBio 8:e00899-17. doi: 10.1128/mBio.00899-17 [DOI] [PMC free article] [PubMed] [Google Scholar]
242. Cheng YL, Kuo CF, Lu SL, Omori H, Wu YN, Hsieh CL, Noda T, Wu SR, Anderson R, Lin CF, Chen CL, Wu JJ, Lin YS. 2019. Group A Streptococcus induces LAPosomes via SLO/β1 integrin/NOX2/ROS pathway in endothelial cells that are ineffective in bacterial killing and suppress xenophagy. mBio 10:e02148-19. doi: 10.1128/mBio.02148-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
243. Hsieh CL, Hsieh SY, Huang HM, Lu SL, Omori H, Zheng PX, Ho YN, Cheng YL, Lin YS, Chiang-Ni C, Tsai PJ, Wang SY, Liu CC, Noda T, Wu JJ. 2020. Nicotinamide increases intracellular NAD⁺ content to enhance autophagy-mediated group A streptococcal clearance in endothelial cells. Front Microbiol 11:117. doi: 10.3389/fmicb.2020.00117 [DOI] [PMC free article] [PubMed] [Google Scholar]
244. Lu SL, Omori H, Zhou Y, Lin YS, Liu CC, Wu JJ, Noda T. 2022. VEGF-mediated augmentation of autophagic and lysosomal activity in endothelial cells defends against intracellular Streptococcus pyogenes. mBio 13:e0123322. doi: 10.1128/mbio.01233-22 [DOI] [PMC free article] [PubMed] [Google Scholar]
245. Perrin AJ, Jiang X, Birmingham CL, So NSY, Brumell JH. 2004. Recognition of bacteria in the cytosol of mammalian cells by the ubiquitin system. Curr Biol 14:806–811. doi: 10.1016/j.cub.2004.04.033 [DOI] [PubMed] [Google Scholar]
246. Stolz A, Ernst A, Dikic I. 2014. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol 16:495–501. doi: 10.1038/ncb2979 [DOI] [PubMed] [Google Scholar]
247. Thurston TLM, Ryzhakov G, Bloor S, von Muhlinen N, Randow F. 2009. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol 10:1215–1221. doi: 10.1038/ni.1800 [DOI] [PubMed] [Google Scholar]
248. Thurston TLM, Wandel MP, von Muhlinen N, Foeglein A, Randow F. 2012. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482:414–418. doi: 10.1038/nature10744 [DOI] [PMC free article] [PubMed] [Google Scholar]
249. Huett A, Heath RJ, Begun J, Sassi SO, Baxt LA, Vyas JM, Goldberg MB, Xavier RJ. 2012. The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella typhimurium. Cell Host Microbe 12:778–790. doi: 10.1016/j.chom.2012.10.019 [DOI] [PMC free article] [PubMed] [Google Scholar]
250. Noad J, von der Malsburg A, Pathe C, Michel MA, Komander D, Randow F. 2017. LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-κB. Nat Microbiol 2:17063. doi: 10.1038/nmicrobiol.2017.63 [DOI] [PMC free article] [PubMed] [Google Scholar]
251. Polajnar M, Dietz MS, Heilemann M, Behrends C. 2017. Expanding the host cell ubiquitylation machinery targeting cytosolic Salmonella. EMBO Rep 18:1572–1585. doi: 10.15252/embr.201643851 [DOI] [PMC free article] [PubMed] [Google Scholar]
252. Sharma V, Verma S, Seranova E, Sarkar S, Kumar D. 2018. Selective autophagy and xenophagy in infection and disease. Front Cell Dev Biol 6:147. doi: 10.3389/fcell.2018.00147 [DOI] [PMC free article] [PubMed] [Google Scholar]
253. Deretic V, Saitoh T, Akira S. 2013. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 13:722–737. doi: 10.1038/nri3532 [DOI] [PMC free article] [PubMed] [Google Scholar]
254. Matsumoto G, Wada K, Okuno M, Kurosawa M, Nukina N. 2011. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 44:279–289. doi: 10.1016/j.molcel.2011.07.039 [DOI] [PubMed] [Google Scholar]
255. Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P, Zaffagnini G, Wild P, Martens S, Wagner SA, Youle RJ, Dikic I. 2016. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci U S A 113:4039–4044. doi: 10.1073/pnas.1523926113 [DOI] [PMC free article] [PubMed] [Google Scholar]
256. Bell SL, Lopez KL, Cox JS, Patrick KL, Watson RO. 2021. Galectin-8 senses phagosomal damage and recruits selective autophagy adapter TAX1BP1 to control Mycobacterium tuberculosis infection in macrophages. mBio 12:e0187120. doi: 10.1128/mBio.01871-20 [DOI] [PMC free article] [PubMed] [Google Scholar]
257. Weng IC, Chen HL, Lo TH, Lin WH, Chen HY, Hsu DK, Liu FT. 2018. Cytosolic galectin-3 and -8 regulate antibacterial autophagy through differential recognition of host glycans on damaged phagosomes. Glycobiology 28:392–405. doi: 10.1093/glycob/cwy017 [DOI] [PubMed] [Google Scholar]
258. Hancz D, Westerlund E, Valfridsson C, Aemero GM, Bastiat-Sempe B, Orning P, Lien E, Wessels MR, Persson JJ. 2019. Streptolysin O induces the ubiquitination and degradation of pro-IL-1β. J Innate Immun 11:457–468. doi: 10.1159/000496403 [DOI] [PMC free article] [PubMed] [Google Scholar]
259. Ktistakis NT, Tooze SA. 2016. Digesting the expanding mechanisms of autophagy. Trends Cell Biol 26:624–635. doi: 10.1016/j.tcb.2016.03.006 [DOI] [PubMed] [Google Scholar]
260. Zhao YG, Zhang H. 2018. Formation and maturation of autophagosomes in higher eukaryotes: a social network. Curr Opin Cell Biol 53:29–36. doi: 10.1016/j.ceb.2018.04.003 [DOI] [PubMed] [Google Scholar]
261. Jiang P, Nishimura T, Sakamaki Y, Itakura E, Hatta T, Natsume T, Mizushima N. 2014. The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17. Mol Biol Cell 25:1327–1337. doi: 10.1091/mbc.E13-08-0447 [DOI] [PMC free article] [PubMed] [Google Scholar]
262. Langemeyer L, Fröhlich F, Ungermann C. 2018. Rab GTPase function in endosome and lysosome biogenesis. Trends Cell Biol 28:957–970. doi: 10.1016/j.tcb.2018.06.007 [DOI] [PubMed] [Google Scholar]
263. Heckmann BL, Green DR. 2019. LC3-associated phagocytosis at a glance. J Cell Sci 132:jcs222984. doi: 10.1242/jcs.222984 [DOI] [PMC free article] [PubMed] [Google Scholar]
264. Upadhyay S, Philips JA. 2019. LC3-associated phagocytosis: host defense and microbial response. Curr Opin Immunol 60:81–90. doi: 10.1016/j.coi.2019.04.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
265. Martinez J, Malireddi RKS, Lu Q, Cunha LD, Pelletier S, Gingras S, Orchard R, Guan JL, Tan H, Peng J, Kanneganti TD, Virgin HW, Green DR. 2015. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat Cell Biol 17:893–906. doi: 10.1038/ncb3192 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
266. Gluschko A, Herb M, Wiegmann K, Krut O, Neiss WF, Utermöhlen O, Krönke M, Schramm M. 2018. The β2 integrin Mac-1 induces protective LC3-associated phagocytosis of Listeria monocytogenes. Cell Host Microbe 23:324–337. doi: 10.1016/j.chom.2018.01.018 [DOI] [PubMed] [Google Scholar]
267. Kim ML, Martin WJ, Minigo G, Keeble JL, Garnham AL, Pacini G, Smyth GK, Speed TP, Carapetis J, Wicks IP. 2018. Dysregulated IL-1β-GM-CSF axis in acute rheumatic fever that is limited by hydroxychloroquine. Circulation 138:2648–2661. doi: 10.1161/CIRCULATIONAHA.118.033891 [DOI] [PubMed] [Google Scholar]
268. Norrby-Teglund A, Chatellier S, Low DE, McGeer A, Green K, Kotb M. 2000. Host variation in cytokine responses to superantigens determine the severity of invasive group A streptococcal infection. Eur J Immunol 30:3247–3255. doi: [DOI] [PubMed] [Google Scholar]
269. Fitzgerald KA, Kagan JC. 2020. Toll-like receptors and the control of immunity. Cell 180:1044–1066. doi: 10.1016/j.cell.2020.02.041 [DOI] [PMC free article] [PubMed] [Google Scholar]
270. Li D, Wu M. 2021. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther 6:291. doi: 10.1038/s41392-021-00687-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
271. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K, Akira S. 1999. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 11:443–451. doi: 10.1016/s1074-7613(00)80119-3 [DOI] [PubMed] [Google Scholar]
272. Eigenbrod T, Pelka K, Latz E, Kreikemeyer B, Dalpke AH. 2015. TLR8 senses bacterial RNA in human monocytes and plays a nonredundant role for recognition of Streptococcus pyogenes. J Immunol 195:1092–1099. doi: 10.4049/jimmunol.1403173 [DOI] [PubMed] [Google Scholar]
273. Fieber C, Janos M, Koestler T, Gratz N, Li XD, Castiglia V, Aberle M, Sauert M, Wegner M, Alexopoulou L, Kirschning CJ, Chen ZJ, von Haeseler A, Kovarik P. 2015. Innate immune response to Streptococcus pyogenes depends on the combined activation of TLR13 and TLR2. PLoS One 10:e0119727. doi: 10.1371/journal.pone.0119727 [DOI] [PMC free article] [PubMed] [Google Scholar]
274. Hafner A, Kolbe U, Freund I, Castiglia V, Kovarik P, Poth T, Herster F, Weigand MA, Weber ANR, Dalpke AH, Eigenbrod T. 2019. Crucial role of nucleic acid sensing via endosomal Toll-like receptors for the defense of Streptococcus pyogenes in vitro and in vivo. Front Immunol 10:198. doi: 10.3389/fimmu.2019.00198 [DOI] [PMC free article] [PubMed] [Google Scholar]
275. Zinkernagel AS, Hruz P, Uchiyama S, von Köckritz-Blickwede M, Schuepbach RA, Hayashi T, Carson DA, Nizet V. 2012. Importance of Toll-like receptor 9 in host defense against M1T1 group A Streptococcus infections. J Innate Immun 4:213–218. doi: 10.1159/000329550 [DOI] [PMC free article] [PubMed] [Google Scholar]
276. Movert E, Bolarin JS, Valfridsson C, Velarde J, Skrede S, Nekludov M, Hyldegaard O, Arnell P, Svensson M, Norrby-Teglund A, Cho KH, Elhaik E, Wessels MR, Råberg L, Carlsson F. 2023. Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability. Nat Commun 14:4008. doi: 10.1038/s41467-023-39771-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
277. Fieber C, Kovarik P. 2014. Responses of innate immune cells to group A Streptococcus. Front Cell Infect Microbiol 4:140. doi: 10.3389/fcimb.2014.00140 [DOI] [PMC free article] [PubMed] [Google Scholar]
278. Gratz N, Hartweger H, Matt U, Kratochvill F, Janos M, Sigel S, Drobits B, Li XD, Knapp S, Kovarik P. 2011. Type I interferon production induced by Streptococcus pyogenes-derived nucleic acids is required for host protection. PLoS Pathog 7:e1001345. doi: 10.1371/journal.ppat.1001345 [DOI] [PMC free article] [PubMed] [Google Scholar]
279. Gratz N, Siller M, Schaljo B, Pirzada ZA, Gattermeier I, Vojtek I, Kirschning CJ, Wagner H, Akira S, Charpentier E, Kovarik P. 2008. Group A Streptococcus activates type I interferon production and MyD88-dependent signaling without involvement of TLR2, TLR4, and TLR9. J Biol Chem 283:19879–19887. doi: 10.1074/jbc.M802848200 [DOI] [PMC free article] [PubMed] [Google Scholar]
280. Evavold CL, Kagan JC. 2019. Inflammasomes: threat-assessment organelles of the innate immune system. Immunity 51:609–624. doi: 10.1016/j.immuni.2019.08.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
281. Richter J, Brouwer S, Schroder K, Walker MJ. 2021. Inflammasome activation and IL-1β signalling in group A Streptococcus disease. Cell Microbiol 23:e13373. doi: 10.1111/cmi.13373 [DOI] [PubMed] [Google Scholar]
282. Johnson DC, Taabazuing CY, Okondo MC, Chui AJ, Rao SD, Brown FC, Reed C, Peguero E, de Stanchina E, Kentsis A, Bachovchin DA. 2018. DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat Med 24:1151–1156. doi: 10.1038/s41591-018-0082-y [DOI] [PMC free article] [PubMed] [Google Scholar]
283. Swanson KV, Deng M, Ting JPY. 2019. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19:477–489. doi: 10.1038/s41577-019-0165-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
284. Duncan JA, Bergstralh DT, Wang Y, Willingham SB, Ye Z, Zimmermann AG, Ting JPY. 2007. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci U S A 104:8041–8046. doi: 10.1073/pnas.0611496104 [DOI] [PMC free article] [PubMed] [Google Scholar]
285. Hafner-Bratkovič I, Sušjan P, Lainšček D, Tapia-Abellán A, Cerović K, Kadunc L, Angosto-Bazarra D, Pelegrin P, Jerala R. 2018. NLRP3 lacking the leucine-rich repeat domain can be fully activated via the canonical inflammasome pathway. Nat Commun 9:5182. doi: 10.1038/s41467-018-07573-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
286. He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J. 2015. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res 25:1285–1298. doi: 10.1038/cr.2015.139 [DOI] [PMC free article] [PubMed] [Google Scholar]
287. Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J. 2016. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535:153–158. doi: 10.1038/nature18629 [DOI] [PMC free article] [PubMed] [Google Scholar]
288. Yang J, Liu Z, Xiao TS. 2017. Post-translational regulation of inflammasomes. Cell Mol Immunol 14:65–79. doi: 10.1038/cmi.2016.29 [DOI] [PMC free article] [PubMed] [Google Scholar]
289. Zangiabadi S, Abdul-Sater AA. 2022. Regulation of the NLRP3 inflammasome by posttranslational modifications. J Immunol 208:286–292. doi: 10.4049/jimmunol.2100734 [DOI] [PubMed] [Google Scholar]
290. Perregaux D, Gabel CA. 1994. Interleukin-1β maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J Biol Chem 269:15195–15203. [PubMed] [Google Scholar]
291. Surprenant A, Rassendren F, Kawashima E, North RA, Buell G. 1996. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272:735–738. doi: 10.1126/science.272.5262.735 [DOI] [PubMed] [Google Scholar]
292. Walev I, Reske K, Palmer M, Valeva A, Bhakdi S. 1995. Potassium-inhibited processing of IL-1β in human monocytes. EMBO J 14:1607–1614. doi: 10.1002/j.1460-2075.1995.tb07149.x [DOI] [PMC free article] [PubMed] [Google Scholar]
293. Westerlund E, Valfridsson C, Yi DX, Persson JJ. 2019. The secreted virulence factor NADase of group A Streptococcus inhibits P2X7 receptor-mediated release of IL-1β. Front Immunol 10:1385. doi: 10.3389/fimmu.2019.01385 [DOI] [PMC free article] [PubMed] [Google Scholar]
294. Madden JC, Ruiz N, Caparon M. 2001. Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in Gram-positive bacteria. Cell 104:143–152. doi: 10.1016/s0092-8674(01)00198-2 [DOI] [PubMed] [Google Scholar]
295. Hancz D, Westerlund E, Bastiat-Sempe B, Sharma O, Valfridsson C, Meyer L, Love JF, O’Seaghdha M, Wessels MR, Persson JJ. 2017. Inhibition of inflammasome-dependent interleukin 1β production by streptococcal NAD⁺-glycohydrolase: evidence for extracellular activity. mBio 8:e00756-17. doi: 10.1128/mBio.00756-17 [DOI] [PMC free article] [PubMed] [Google Scholar]
296. Richter J, Monteleone MM, Cork AJ, Barnett TC, Nizet V, Brouwer S, Schroder K, Walker MJ. 2021. Streptolysins are the primary inflammasome activators in macrophages during Streptococcus pyogenes infection. Immunol Cell Biol 99:1040–1052. doi: 10.1111/imcb.12499 [DOI] [PubMed] [Google Scholar]
297. Chella Krishnan K, Mukundan S, Alagarsamy J, Hur J, Nookala S, Siemens N, Svensson M, Hyldegaard O, Norrby-Teglund A, Kotb M. 2016. Genetic architecture of group A streptococcal necrotizing soft tissue infections in the mouse. PLoS Pathog 12:e1005732. doi: 10.1371/journal.ppat.1005732 [DOI] [PMC free article] [PubMed] [Google Scholar]
298. Kapur V, Majesky MW, Li LL, Black RA, Musser JM. 1993. Cleavage of interleukin 1β (IL-1β) precursor to produce active IL-1β by a conserved extracellular cysteine protease from Streptococcus pyogenes. Proc Natl Acad Sci U S A 90:7676–7680. doi: 10.1073/pnas.90.16.7676 [DOI] [PMC free article] [PubMed] [Google Scholar]
299. Johnson AF, Sands JS, Trivedi KM, Russell R, LaRock DL, LaRock CN. 2023. Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection. PLoS Pathog 19:e1011321. doi: 10.1371/journal.ppat.1011321 [DOI] [PMC free article] [PubMed] [Google Scholar]
300. LaRock CN, Todd J, LaRock DL, Olson J, O’Donoghue AJ, Robertson AAB, Cooper MA, Hoffman HM, Nizet V. 2016. IL-1β is an innate immune sensor of microbial proteolysis. Sci Immunol 1:eaah3539. doi: 10.1126/sciimmunol.aah3539 [DOI] [PMC free article] [PubMed] [Google Scholar]
301. LaRock DL, Russell R, Johnson AF, Wilde S, LaRock CN. 2020. Group A Streptococcus infection of the nasopharynx requires proinflammatory signaling through the interleukin-1 receptor. Infect Immun 88:e00356-20. doi: 10.1128/IAI.00356-20 [DOI] [PMC free article] [PubMed] [Google Scholar]
302. Nakagawa I, Nakata M, Kawabata S, Hamada S. 2001. Cytochrome c-mediated caspase-9 activation triggers apoptosis in Streptococcus pyogenes-infected epithelial cells. Cell Microbiol 3:395–405. doi: 10.1046/j.1462-5822.2001.00122.x [DOI] [PubMed] [Google Scholar]
303. Jorgensen I, Rayamajhi M, Miao EA. 2017. Programmed cell death as a defence against infection. Nat Rev Immunol 17:151–164. doi: 10.1038/nri.2016.147 [DOI] [PMC free article] [PubMed] [Google Scholar]
304. Booty LM, Bryant CE. 2022. Gasdermin D and beyond - gasdermin-mediated pyroptosis in bacterial infections. J Mol Biol 434:167409. doi: 10.1016/j.jmb.2021.167409 [DOI] [PubMed] [Google Scholar]
305. Keestra-Gounder AM, Nagao PE. 2023. Inflammasome activation by Gram-positive bacteria: mechanisms of activation and regulation. Front Immunol 14:1075834. doi: 10.3389/fimmu.2023.1075834 [DOI] [PMC free article] [PubMed] [Google Scholar]
306. Broz P, Pelegrín P, Shao F. 2020. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol 20:143–157. doi: 10.1038/s41577-019-0228-2 [DOI] [PubMed] [Google Scholar]
307. Liu X, Xia S, Zhang Z, Wu H, Lieberman J. 2021. Channelling inflammation: gasdermins in physiology and disease. Nat Rev Drug Discov 20:384–405. doi: 10.1038/s41573-021-00154-z [DOI] [PMC free article] [PubMed] [Google Scholar]
308. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM. 2015. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666–671. doi: 10.1038/nature15541 [DOI] [PubMed] [Google Scholar]

[B1] 1. Carapetis JR, Steer AC, Mulholland EK, Weber M. 2005. The global burden of group A streptococcal diseases. Lancet Infect Dis 5:685–694. doi: 10.1016/S1473-3099(05)70267-X [DOI] [PubMed] [Google Scholar]

[B2] 2. Brouwer S, Rivera-Hernandez T, Curren BF, Harbison-Price N, De Oliveira DMP, Jespersen MG, Davies MR, Walker MJ. 2023. Pathogenesis, epidemiology and control of group A Streptococcus infection. Nat Rev Microbiol 21:619. doi: 10.1038/s41579-023-00939-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B3] 3. Efstratiou A, Lamagni T. 2022. Epidemiology of Streptococcus pyogenes. In Ferretti JJ, Stevens DL, Fischetti VA (ed), Streptococcus pyogenes: basic biology to clinical manifestations, 2nd ed. Oklahoma City (OK). [Google Scholar]

[B4] 4. Pancholi V. 2019. Group A Streptococcus-mediated host cell signaling. Microbiol Spectr 7. doi: 10.1128/microbiolspec.GPP3-0021-2018 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B5] 5. Wang B, Cleary PP. 2019. Intracellular invasion by Streptococcus pyogenes: invasins, host receptors, and relevance to human disease. Microbiol Spectr 7. doi: 10.1128/microbiolspec.GPP3-0049-2018 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B6] 6. Wilkening RV, Langouët-Astrié C, Severn MM, Federle MJ, Horswill AR. 2023. Identifying genetic determinants of Streptococcus pyogenes-host interactions in a murine intact skin infection model. Cell Rep 42:113332. doi: 10.1016/j.celrep.2023.113332 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B7] 7. Kachroo P, Eraso JM, Olsen RJ, Zhu L, Kubiak SL, Pruitt L, Yerramilli P, Cantu CC, Ojeda Saavedra M, Pensar J, Corander J, Jenkins L, Kao L, Granillo A, Porter AR, DeLeo FR, Musser JM. 2020. New pathogenesis mechanisms and translational leads identified by multidimensional analysis of necrotizing myositis in primates. mBio 11:e03363-19. doi: 10.1128/mBio.03363-19 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B8] 8. Okumura CYM, Nizet V. 2014. Subterfuge and sabotage: evasion of host innate defenses by invasive Gram-positive bacterial pathogens. Annu Rev Microbiol 68:439–458. doi: 10.1146/annurev-micro-092412-155711 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B9] 9. Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. 2019. New insights into the immune functions of complement. Nat Rev Immunol 19:503–516. doi: 10.1038/s41577-019-0168-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[B10] 10. Syed S, Viazmina L, Mager R, Meri S, Haapasalo K. 2020. Streptococci and the complement system: interplay during infection, inflammation and autoimmunity. FEBS Lett 594:2570–2585. doi: 10.1002/1873-3468.13872 [DOI] [PubMed] [Google Scholar]

[B11] 11. Dunkelberger JR, Song W-C. 2010. Complement and its role in innate and adaptive immune responses. Cell Res 20:34–50. doi: 10.1038/cr.2009.139 [DOI] [PubMed] [Google Scholar]

[B12] 12. Nordenfelt P, Waldemarson S, Linder A, Mörgelin M, Karlsson C, Malmström J, Björck L. 2012. Antibody orientation at bacterial surfaces is related to invasive infection. J Exp Med 209:2367–2381. doi: 10.1084/jem.20120325 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B13] 13. Honda-Ogawa M, Sumitomo T, Mori Y, Hamd DT, Ogawa T, Yamaguchi M, Nakata M, Kawabata S. 2017. Streptococcus pyogenes endopeptidase O contributes to evasion from complement-mediated bacteriolysis via binding to human complement factor C1q. J Biol Chem 292:4244–4254. doi: 10.1074/jbc.M116.749275 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B14] 14. Collin M, Svensson MD, Sjöholm AG, Jensenius JC, Sjöbring U, Olsén A. 2002. EndoS and SpeB from Streptococcus pyogenes inhibit immunoglobulin-mediated opsonophagocytosis. Infect Immun 70:6646–6651. doi: 10.1128/IAI.70.12.6646-6651.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B15] 15. Lei B, DeLeo FR, Hoe NP, Graham MR, Mackie SM, Cole RL, Liu M, Hill HR, Low DE, Federle MJ, Scott JR, Musser JM. 2001. Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis. Nat Med 7:1298–1305. doi: 10.1038/nm1201-1298 [DOI] [PubMed] [Google Scholar]

[B16] 16. Su YF, Chuang WJ, Wang SM, Chen WY, Chiang-Ni C, Lin YS, Wu JJ, Liu CC. 2011. The deficient cleavage of M protein-bound IgG by IdeS: insight into the escape of Streptococcus pyogenes from antibody-mediated immunity. Mol Immunol 49:134–142. doi: 10.1016/j.molimm.2011.08.002 [DOI] [PubMed] [Google Scholar]

[B17] 17. Sjögren J, Okumura CYM, Collin M, Nizet V, Hollands A. 2011. Study of the IgG endoglycosidase EndoS in group A streptococcal phagocyte resistance and virulence. BMC Microbiol 11:120. doi: 10.1186/1471-2180-11-120 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B18] 18. Aghababa H, Ting YT, Pilapitiya D, Loh JMS, Young PG, Proft T. 2022. Complement evasion factor (CEF), a novel immune evasion factor of Streptococcus pyogenes. Virulence 13:225–240. doi: 10.1080/21505594.2022.2027629 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B19] 19. Honda-Ogawa M, Ogawa T, Terao Y, Sumitomo T, Nakata M, Ikebe K, Maeda Y, Kawabata S. 2013. Cysteine proteinase from Streptococcus pyogenes enables evasion of innate immunity via degradation of complement factors. J Biol Chem 288:15854–15864. doi: 10.1074/jbc.M113.469106 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B20] 20. Kuo CF, Lin YS, Chuang WJ, Wu JJ, Tsao N. 2008. Degradation of complement 3 by streptococcal pyrogenic exotoxin B inhibits complement activation and neutrophil opsonophagocytosis. Infect Immun 76:1163–1169. doi: 10.1128/IAI.01116-07 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B21] 21. Kuo CF, Tsao N, Cheng MH, Yang HC, Wang YC, Chen YP, Lin KJ. 2015. Application of the C3-binding motif of streptococcal pyrogenic exotoxin B to protect mice from invasive group A streptococcal infection. PLoS One 10:e0117268. doi: 10.1371/journal.pone.0117268 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B22] 22. Carlsson F, Sandin C, Lindahl G. 2005. Human fibrinogen bound to Streptococcus pyogenes M protein inhibits complement deposition via the classical pathway. Mol Microbiol 56:28–39. doi: 10.1111/j.1365-2958.2005.04527.x [DOI] [PubMed] [Google Scholar]

[B23] 23. Courtney HS, Hasty DL, Dale JB. 2006. Anti-phagocytic mechanisms of Streptococcus pyogenes: binding of fibrinogen to M-related protein. Mol Microbiol 59:936–947. doi: 10.1111/j.1365-2958.2005.04977.x [DOI] [PubMed] [Google Scholar]

[B24] 24. Lynskey NN, Reglinski M, Calay D, Siggins MK, Mason JC, Botto M, Sriskandan S. 2017. Multi-functional mechanisms of immune evasion by the streptococcal complement inhibitor C5a peptidase. PLoS Pathog 13:e1006493. doi: 10.1371/journal.ppat.1006493 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B25] 25. McKenna S, Aylward F, Miliara X, Lau RJ, Huemer CB, Giblin SP, Huse KK, Liang M, Reeves L, Pearson M, Xu Y, Rouse SL, Pease JE, Sriskandan S, Kagawa TF, Cooney J, Matthews S. 2023. The protease associated (PA) domain in ScpA from Streptococcus pyogenes plays a role in substrate recruitment. Biochim Biophys Acta Proteins Proteom 1871:140946. doi: 10.1016/j.bbapap.2023.140946 [DOI] [PubMed] [Google Scholar]

[B26] 26. Cleary PP, Prahbu U, Dale JB, Wexler DE, Handley J. 1992. Streptococcal C5a peptidase is a highly specific endopeptidase. Infect Immun 60:5219–5223. doi: 10.1128/iai.60.12.5219-5223.1992 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B27] 27. Terao Y, Yamaguchi M, Hamada S, Kawabata S. 2006. Multifunctional glyceraldehyde-3-phosphate dehydrogenase of Streptococcus pyogenes is essential for evasion from neutrophils. J Biol Chem 281:14215–14223. doi: 10.1074/jbc.M513408200 [DOI] [PubMed] [Google Scholar]

[B28] 28. Berends ETM, Dekkers JF, Nijland R, Kuipers A, Soppe JA, van Strijp JAG, Rooijakkers SHM. 2013. Distinct localization of the complement C5b-9 complex on Gram-positive bacteria. Cell Microbiol 15:1955–1968. doi: 10.1111/cmi.12170 [DOI] [PubMed] [Google Scholar]

[B29] 29. Akesson P, Sjöholm AG, Björck L. 1996. Protein SIC, a novel extracellular protein of Streptococcus pyogenes interfering with complement function. J Biol Chem 271:1081–1088. doi: 10.1074/jbc.271.2.1081 [DOI] [PubMed] [Google Scholar]

[B30] 30. Fernie-King BA, Seilly DJ, Willers C, Würzner R, Davies A, Lachmann PJ. 2001. Streptococcal inhibitor of complement (SIC) inhibits the membrane attack complex by preventing uptake of C567 onto cell membranes. Immunology 103:390–398. doi: 10.1046/j.1365-2567.2001.01249.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[B31] 31. Agrahari G, Liang Z, Glinton K, Lee SW, Ploplis VA, Castellino FJ. 2016. Streptococcus pyogenes employs strain-dependent mechanisms of C3b inactivation to inhibit phagocytosis and killing of bacteria. J Biol Chem 291:9181–9189. doi: 10.1074/jbc.M115.704221 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B32] 32. Fujita T, Nussenzweig V. 1979. The role of C4-binding protein and β1H in proteolysis of C4b and C3b. J Exp Med 150:267–276. doi: 10.1084/jem.150.2.267 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B33] 33. Gigli I, Fujita T, Nussenzweig V. 1979. Modulation of the classical pathway C3 convertase by plasma proteins C4 binding protein and C3b inactivator. Proc Natl Acad Sci U S A 76:6596–6600. doi: 10.1073/pnas.76.12.6596 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B34] 34. Ermert D, Shaughnessy J, Joeris T, Kaplan J, Pang CJ, Kurt-Jones EA, Rice PA, Ram S, Blom AM. 2015. Virulence of group A Streptococci is enhanced by human complement inhibitors. PLoS Pathog 11:e1005043. doi: 10.1371/journal.ppat.1005043 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B35] 35. Ermert D, Laabei M, Weckel A, Mörgelin M, Lundqvist M, Björck L, Ram S, Linse S, Blom AM. 2019. The molecular basis of human IgG-mediated enhancement of C4b-binding protein recruitment to group A Streptococcus. Front Immunol 10:1230. doi: 10.3389/fimmu.2019.01230 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B36] 36. Ermert D, Weckel A, Magda M, Mörgelin M, Shaughnessy J, Rice PA, Björck L, Ram S, Blom AM. 2018. Human IgG increases virulence of Streptococcus pyogenes through complement evasion. J Immunol 200:3495–3505. doi: 10.4049/jimmunol.1800090 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B37] 37. Ly D, Taylor JM, Tsatsaronis JA, Monteleone MM, Skora AS, Donald CA, Maddocks T, Nizet V, West NP, Ranson M, Walker MJ, McArthur JD, Sanderson-Smith ML. 2014. Plasmin(ogen) acquisition by group A Streptococcus protects against C3b-mediated neutrophil killing. J Innate Immun 6:240–250. doi: 10.1159/000353754 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B38] 38. Vercellotti GM, McCarthy JB, Lindholm P, Peterson PK, Jacob HS, Furcht LT. 1985. Extracellular matrix proteins (fibronectin, laminin, and type IV collagen) bind and aggregate bacteria. Am J Pathol 120:13–21. [PMC free article] [PubMed] [Google Scholar]

[B39] 39. Cue D, Dombek PE, Lam H, Cleary PP. 1998. Streptococcus pyogenes serotype M1 encodes multiple pathways for entry into human epithelial cells. Infect Immun 66:4593–4601. doi: 10.1128/IAI.66.10.4593-4601.1998 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B40] 40. Hynes RO. 1992. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69:11–25. doi: 10.1016/0092-8674(92)90115-s [DOI] [PubMed] [Google Scholar]

[B41] 41. Grabovskaya KB, Totoljan AA, Rýc M, Havlícek J, Burova LA, Bícová R. 1980. Adherence of group A streptococci to epithelial cells in tissue culture. Zentralbl Bakteriol A 247:303–314. [PubMed] [Google Scholar]

[B42] 42. Hasty DL, Ofek I, Courtney HS, Doyle RJ. 1992. Multiple adhesins of streptococci. Infect Immun 60:2147–2152. doi: 10.1128/iai.60.6.2147-2152.1992 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B43] 43. Beachey EH, Ofek I. 1976. Epithelial cell binding of group A streptococci by lipoteichoic acid on fimbriae denuded of M protein. J Exp Med 143:759–771. doi: 10.1084/jem.143.4.759 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B44] 44. Ryan PA, Pancholi V, Fischetti VA. 2001. Group A streptococci bind to mucin and human pharyngeal cells through sialic acid-containing receptors. Infect Immun 69:7402–7412. doi: 10.1128/IAI.69.12.7402-7412.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B45] 45. Dale JB, Washburn RG, Marques MB, Wessels MR. 1996. Hyaluronate capsule and surface M protein in resistance to opsonization of group A streptococci. Infect Immun 64:1495–1501. doi: 10.1128/iai.64.5.1495-1501.1996 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B46] 46. Wessels MR, Moses AE, Goldberg JB, DiCesare TJ. 1991. Hyaluronic acid capsule is a virulence factor for mucoid group A streptococci. Proc Natl Acad Sci U S A 88:8317–8321. doi: 10.1073/pnas.88.19.8317 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B47] 47. Schrager HM, Albertí S, Cywes C, Dougherty GJ, Wessels MR. 1998. Hyaluronic acid capsule modulates M protein-mediated adherence and acts as a ligand for attachment of group A Streptococcus to CD44 on human keratinocytes. J Clin Invest 101:1708–1716. doi: 10.1172/JCI2121 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B48] 48. Cywes C, Stamenkovic I, Wessels MR. 2000. CD44 as a receptor for colonization of the pharynx by group A Streptococcus. J Clin Invest 106:995–1002. doi: 10.1172/JCI10195 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B49] 49. Cywes C, Wessels MR. 2001. Group A Streptococcus tissue invasion by CD44-mediated cell signalling. Nature 414:648–652. doi: 10.1038/414648a [DOI] [PubMed] [Google Scholar]

[B50] 50. Beachey EH, Courtney HS. 1987. Bacterial adherence: the attachment of group A streptococci to mucosal surfaces. Rev Infect Dis 9:S475–S481. doi: 10.1093/clinids/9.supplement_5.s475 [DOI] [PubMed] [Google Scholar]

[B51] 51. Courtney HS, von Hunolstein C, Dale JB, Bronze MS, Beachey EH, Hasty DL. 1992. Lipoteichoic acid and M protein: dual adhesins of group A streptococci. Microb Pathog 12:199–208. doi: 10.1016/0882-4010(92)90054-r [DOI] [PubMed] [Google Scholar]

[B52] 52. Okada N, Liszewski MK, Atkinson JP, Caparon M. 1995. Membrane cofactor protein (CD46) is a keratinocyte receptor for the M protein of the group A Streptococcus. Proc Natl Acad Sci U S A 92:2489–2493. doi: 10.1073/pnas.92.7.2489 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B53] 53. Giannakis E, Jokiranta TS, Ormsby RJ, Duthy TG, Male DA, Christiansen D, Fischetti VA, Bagley C, Loveland BE, Gordon DL. 2002. Identification of the streptococcal M protein binding site on membrane cofactor protein (CD46). J Immunol 168:4585–4592. doi: 10.4049/jimmunol.168.9.4585 [DOI] [PubMed] [Google Scholar]

[B54] 54. Abbot EL, Smith WD, Siou GPS, Chiriboga C, Smith RJ, Wilson JA, Hirst BH, Kehoe MA. 2007. Pili mediate specific adhesion of Streptococcus pyogenes to human tonsil and skin. Cell Microbiol 9:1822–1833. doi: 10.1111/j.1462-5822.2007.00918.x [DOI] [PubMed] [Google Scholar]

[B55] 55. Manetti AGO, Zingaretti C, Falugi F, Capo S, Bombaci M, Bagnoli F, Gambellini G, Bensi G, Mora M, Edwards AM, Musser JM, Graviss EA, Telford JL, Grandi G, Margarit I. 2007. Streptococcus pyogenes pili promote pharyngeal cell adhesion and biofilm formation. Mol Microbiol 64:968–983. doi: 10.1111/j.1365-2958.2007.05704.x [DOI] [PubMed] [Google Scholar]

[B56] 56. Rouchon CN, Ly AT, Noto JP, Luo F, Lizano S, Bessen DE. 2017. Incremental contributions of FbaA and other impetigo-associated surface proteins to fitness and virulence of a classical group A streptococcal skin strain. Infect Immun 85:e00374-17. doi: 10.1128/IAI.00374-17 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B57] 57. Hytönen J, Haataja S, Finne J. 2003. Streptococcus pyogenes glycoprotein-binding strepadhesin activity is mediated by a surface-associated carbohydrate-degrading enzyme, pullulanase. Infect Immun 71:784–793. doi: 10.1128/IAI.71.2.784-793.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B58] 58. Terao Y, Kawabata S, Kunitomo E, Murakami J, Nakagawa I, Hamada S. 2001. Fba, a novel fibronectin-binding protein from Streptococcus pyogenes, promotes bacterial entry into epithelial cells, and the fba gene is positively transcribed under the Mga regulator. Mol Microbiol 42:75–86. doi: 10.1046/j.1365-2958.2001.02579.x [DOI] [PubMed] [Google Scholar]

[B59] 59. Jaffe J, Natanson-Yaron S, Caparon MG, Hanski E. 1996. Protein F2, a novel fibronectin-binding protein from Streptococcus pyogenes, possesses two binding domains. Mol Microbiol 21:373–384. doi: 10.1046/j.1365-2958.1996.6331356.x [DOI] [PubMed] [Google Scholar]

[B60] 60. Rocha CL, Fischetti VA. 1997. Identification and characterization of a new protein from Streptococcus pyogenes having homology with fibronectin and fibrinogen binding proteins. Adv Exp Med Biol 418:737–739. doi: 10.1007/978-1-4899-1825-3_173 [DOI] [PubMed] [Google Scholar]

[B61] 61. Rocha CL, Fischetti VA. 1999. Identification and characterization of a novel fibronectin-binding protein on the surface of group A streptococci. Infect Immun 67:2720–2728. doi: 10.1128/IAI.67.6.2720-2728.1999 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B62] 62. Terao Y, Kawabata S, Nakata M, Nakagawa I, Hamada S. 2002. Molecular characterization of a novel fibronectin-binding protein of Streptococcus pyogenes strains isolated from toxic shock-like syndrome patients. J Biol Chem 277:47428–47435. doi: 10.1074/jbc.M209133200 [DOI] [PubMed] [Google Scholar]

[B63] 63. Kreikemeyer B, Klenk M, Podbielski A. 2004. The intracellular status of Streptococcus pyogenes: role of extracellular matrix-binding proteins and their regulation. Int J Med Microbiol 294:177–188. doi: 10.1016/j.ijmm.2004.06.017 [DOI] [PubMed] [Google Scholar]

[B64] 64. Courtney HS, Dale JB, Hasty DI. 1996. Differential effects of the streptococcal fibronectin-binding protein, FBP54, on adhesion of group A streptococci to human buccal cells and HEp-2 tissue culture cells. Infect Immun 64:2415–2419. doi: 10.1128/iai.64.7.2415-2419.1996 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B65] 65. Kawabata S, Kunitomo E, Terao Y, Nakagawa I, Kikuchi K, Totsuka K, Hamada S. 2001. Systemic and mucosal immunizations with fibronectin-binding protein FBP54 induce protective immune responses against Streptococcus pyogenes challenge in mice. Infect Immun 69:924–930. doi: 10.1128/IAI.69.2.924-930.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B66] 66. Cue D, Lam H, Cleary PP. 2001. Genetic dissection of the Streptococcus pyogenes M1 protein: regions involved in fibronectin binding and intracellular invasion. Microb Pathog 31:231–242. doi: 10.1006/mpat.2001.0467 [DOI] [PubMed] [Google Scholar]

[B67] 67. Frick IM, Crossin KL, Edelman GM, Björck L. 1995. Protein H-a bacterial surface protein with affinity for both immunoglobulin and fibronectin type III domains. EMBO J 14:1674–1679. doi: 10.1002/j.1460-2075.1995.tb07156.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[B68] 68. Cue D, Southern SO, Southern PJ, Prabhakar J, Lorelli W, Smallheer JM, Mousa SA, Cleary PP. 2000. A nonpeptide integrin antagonist can inhibit epithelial cell ingestion of Streptococcus pyogenes by blocking formation of integrin α5β1-fibronectin-M1 protein complexes. Proc Natl Acad Sci U S A 97:2858–2863. doi: 10.1073/pnas.050587897 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B69] 69. Pancholi V, Fischetti VA. 1992. A major surface protein on group A streptococci is a glyceraldehyde-3-phosphate-dehydrogenase with multiple binding activity. J Exp Med 176:415–426. doi: 10.1084/jem.176.2.415 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B70] 70. Jin H, Song YP, Boel G, Kochar J, Pancholi V. 2005. Group A streptococcal surface GAPDH, SDH, recognizes uPAR/CD87 as its receptor on the human pharyngeal cell and mediates bacterial adherence to host cells. J Mol Biol 350:27–41. doi: 10.1016/j.jmb.2005.04.063 [DOI] [PubMed] [Google Scholar]

[B71] 71. Caswell CC, Oliver-Kozup H, Han R, Lukomska E, Lukomski S. 2010. Scl1, the multifunctional adhesin of group A Streptococcus, selectively binds cellular fibronectin and laminin, and mediates pathogen internalization by human cells. FEMS Microbiol Lett 303:61–68. doi: 10.1111/j.1574-6968.2009.01864.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[B72] 72. Hanski E, Caparon M. 1992. Protein F, a fibronectin-binding protein, is an adhesin of the group A Streptococcus Streptococcus pyogenes. Proc Natl Acad Sci U S A 89:6172–6176. doi: 10.1073/pnas.89.13.6172 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B73] 73. Talay SR, Valentin-Weigand P, Jerlström PG, Timmis KN, Chhatwal GS. 1992. Fibronectin-binding protein of Streptococcus pyogenes: sequence of the binding domain involved in adherence of streptococci to epithelial cells. Infect Immun 60:3837–3844. doi: 10.1128/iai.60.9.3837-3844.1992 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B74] 74. Talay SR, Zock A, Rohde M, Molinari G, Oggioni M, Pozzi G, Guzman CA, Chhatwal GS. 2000. Co-operative binding of human fibronectin to Sfbl protein triggers streptococcal invasion into respiratory epithelial cells. Cell Microbiol 2:521–535. doi: 10.1046/j.1462-5822.2000.00076.x [DOI] [PubMed] [Google Scholar]

[B75] 75. Kreikemeyer B, Talay SR, Chhatwal GS. 1995. Characterization of a novel fibronectin-binding surface protein in group A streptococci. Mol Microbiol 17:137–145. doi: 10.1111/j.1365-2958.1995.mmi_17010137.x [DOI] [PubMed] [Google Scholar]

[B76] 76. Jeng A, Sakota V, Li Z, Datta V, Beall B, Nizet V. 2003. Molecular genetic analysis of a group A Streptococcus operon encoding serum opacity factor and a novel fibronectin-binding protein, SfbX. J Bacteriol 185:1208–1217. doi: 10.1128/JB.185.4.1208-1217.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B77] 77. Rakonjac JV, Robbins JC, Fischetti VA. 1995. DNA sequence of the serum opacity factor of group A streptococci: identification of a fibronectin-binding repeat domain. Infect Immun 63:622–631. doi: 10.1128/iai.63.2.622-631.1995 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B78] 78. Courtney HS, Hasty DL, Li Y, Chiang HC, Thacker JL, Dale JB. 1999. Serum opacity factor is a major fibronectin-binding protein and a virulence determinant of M type 2 Streptococcus pyogenes. Mol Microbiol 32:89–98. doi: 10.1046/j.1365-2958.1999.01328.x [DOI] [PubMed] [Google Scholar]

[B79] 79. Oehmcke S, Podbielski A, Kreikemeyer B. 2004. Function of the fibronectin-binding serum opacity factor of Streptococcus pyogenes in adherence to epithelial cells. Infect Immun 72:4302–4308. doi: 10.1128/IAI.72.7.4302-4308.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B80] 80. Podbielski A, Woischnik M, Leonard BA, Schmidt KH. 1999. Characterization of nra, a global negative regulator gene in group A streptococci. Mol Microbiol 31:1051–1064. doi: 10.1046/j.1365-2958.1999.01241.x [DOI] [PubMed] [Google Scholar]

[B81] 81. Kreikemeyer B, Nakata M, Oehmcke S, Gschwendtner C, Normann J, Podbielski A. 2005. Streptococcus pyogenes collagen type I-binding Cpa surface protein. Expression profile, binding characteristics, biological functions, and potential clinical impact. J Biol Chem 280:33228–33239. doi: 10.1074/jbc.M502896200 [DOI] [PubMed] [Google Scholar]

[B82] 82. Lukomski S, Nakashima K, Abdi I, Cipriano VJ, Ireland RM, Reid SD, Adams GG, Musser JM. 2000. Identification and characterization of the scl gene encoding a group A Streptococcus extracellular protein virulence factor with similarity to human collagen. Infect Immun 68:6542–6553. doi: 10.1128/IAI.68.12.6542-6553.2000 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B83] 83. Humtsoe JO, Kim JK, Xu Y, Keene DR, Höök M, Lukomski S, Wary KK. 2005. A streptococcal collagen-like protein interacts with the α2β1 integrin and induces intracellular signaling. J Biol Chem 280:13848–13857. doi: 10.1074/jbc.M410605200 [DOI] [PubMed] [Google Scholar]

[B84] 84. Caswell CC, Barczyk M, Keene DR, Lukomska E, Gullberg DE, Lukomski S. 2008. Identification of the first prokaryotic collagen sequence motif that mediates binding to human collagen receptors, integrins α2β1 and α11β1. J Biol Chem 283:36168–36175. doi: 10.1074/jbc.M806865200 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B85] 85. Lukomski S, Nakashima K, Abdi I, Cipriano VJ, Shelvin BJ, Graviss EA, Musser JM. 2001. Identification and characterization of a second extracellular collagen-like protein made by group A Streptococcus: control of production at the level of translation. Infect Immun 69:1729–1738. doi: 10.1128/IAI.69.3.1729-1738.2001 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B86] 86. Squeglia F, Bachert B, De Simone A, Lukomski S, Berisio R. 2014. The crystal structure of the streptococcal collagen-like protein 2 globular domain from invasive M3-type group A Streptococcus shows significant similarity to immunomodulatory HIV protein gp41. J Biol Chem 289:5122–5133. doi: 10.1074/jbc.M113.523597 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B87] 87. Terao Y, Kawabata S, Kunitomo E, Nakagawa I, Hamada S. 2002. Novel laminin-binding protein of Streptococcus pyogenes, Lbp, is involved in adhesion to epithelial cells. Infect Immun 70:993–997. doi: 10.1128/IAI.70.2.993-997.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B88] 88. Wahid RM, Yoshinaga M, Nishi J, Maeno N, Sarantuya J, Ohkawa T, Jalil AM, Kobayashi K, Miyata K. 2005. Immune response to a laminin-binding protein (Lmb) in group A streptococcal infection. Pediatr Int 47:196–202. doi: 10.1111/j.1442-200x.2005.02038.x [DOI] [PubMed] [Google Scholar]

[B89] 89. Elsner A, Kreikemeyer B, Braun-Kiewnick A, Spellerberg B, Buttaro BA, Podbielski A. 2002. Involvement of Lsp, a member of the LraI-lipoprotein family in Streptococcus pyogenes, in eukaryotic cell adhesion and internalization. Infect Immun 70:4859–4869. doi: 10.1128/IAI.70.9.4859-4869.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B90] 90. Dahesh S, Nizet V, Cole JN. 2012. Study of streptococcal hemoprotein receptor (Shr) in iron acquisition and virulence of M1T1 group A Streptococcus. Virulence 3:566–575. doi: 10.4161/viru.21933 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B91] 91. Hytönen J, Haataja S, Gerlach D, Podbielski A, Finne J. 2001. The SpeB virulence factor of Streptococcus pyogenes, a multifunctional secreted and cell surface molecule with strepadhesin, laminin-binding and cysteine protease activity. Mol Microbiol 39:512–519. doi: 10.1046/j.1365-2958.2001.02269.x [DOI] [PubMed] [Google Scholar]

[B92] 92. Walker MJ, McArthur JD, McKay F, Ranson M. 2005. Is plasminogen deployed as a Streptococcus pyogenes virulence factor? Trends Microbiol 13:308–313. doi: 10.1016/j.tim.2005.05.006 [DOI] [PubMed] [Google Scholar]

[B93] 93. Pancholi V, Fischetti VA. 1998. α-enolase, a novel strong plasmin(ogen) binding protein on the surface of pathogenic streptococci. J Biol Chem 273:14503–14515. doi: 10.1074/jbc.273.23.14503 [DOI] [PubMed] [Google Scholar]

[B94] 94. Pancholi V, Fontan P, Jin H. 2003. Plasminogen-mediated group A streptococcal adherence to and pericellular invasion of human pharyngeal cells. Microb Pathog 35:293–303. doi: 10.1016/j.micpath.2003.08.004 [DOI] [PubMed] [Google Scholar]

[B95] 95. Siemens N, Patenge N, Otto J, Fiedler T, Kreikemeyer B. 2011. Streptococcus pyogenes M49 plasminogen/plasmin binding facilitates keratinocyte invasion via integrin-integrin-linked kinase (ILK) pathways and protects from macrophage killing. J Biol Chem 286:21612–21622. doi: 10.1074/jbc.M110.202671 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B96] 96. Sumitomo T, Nakata M, Higashino M, Yamaguchi M, Kawabata S. 2016. Group A Streptococcus exploits human plasminogen for bacterial translocation across epithelial barrier via tricellular tight junctions. Sci Rep 7:20069. doi: 10.1038/srep20069 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B97] 97. Mecham RP. 2012. Overview of extracellular matrix. Curr Protoc Cell Biol Chapter 10:10. doi: 10.1002/0471143030.cb1001s57 [DOI] [PubMed] [Google Scholar]

[B98] 98. Dupuy AG, Caron E. 2008. Integrin-dependent phagocytosis: spreading from microadhesion to new concepts. J Cell Sci 121:1773–1783. doi: 10.1242/jcs.018036 [DOI] [PubMed] [Google Scholar]

[B99] 99. Berkower C, Ravins M, Moses AE, Hanski E. 1999. Expression of different group A streptococcal M proteins in an isogenic background demonstrates diversity in adherence to and invasion of eukaryotic cells. Mol Microbiol 31:1463–1475. doi: 10.1046/j.1365-2958.1999.01289.x [DOI] [PubMed] [Google Scholar]

[B100] 100. Dombek PE, Cue D, Sedgewick J, Lam H, Ruschkowski S, Finlay BB, Cleary PP. 1999. High-frequency intracellular invasion of epithelial cells by serotype M1 group A streptococci: M1 protein-mediated invasion and cytoskeletal rearrangements. Mol Microbiol 31:859–870. doi: 10.1046/j.1365-2958.1999.01223.x [DOI] [PubMed] [Google Scholar]

[B101] 101. Molinari G, Talay SR, Valentin-Weigand P, Rohde M, Chhatwal GS. 1997. The fibronectin-binding protein of Streptococcus pyogenes, SfbI, is involved in the internalization of group A streptococci by epithelial cells. Infect Immun 65:1357–1363. doi: 10.1128/iai.65.4.1357-1363.1997 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B102] 102. Ozeri V, Rosenshine I, Mosher DF, Fässler R, Hanski E. 1998. Roles of integrins and fibronectin in the entry of Streptococcus pyogenes into cells via protein F1. Mol Microbiol 30:625–637. doi: 10.1046/j.1365-2958.1998.01097.x [DOI] [PubMed] [Google Scholar]

[B103] 103. Rezcallah MS, Hodges K, Gill DB, Atkinson JP, Wang B, Cleary PP. 2005. Engagement of CD46 and α5β1 integrin by group A streptococci is required for efficient invasion of epithelial cells. Cell Microbiol 7:645–653. doi: 10.1111/j.1462-5822.2004.00497.x [DOI] [PubMed] [Google Scholar]

[B104] 104. Catton EA, Bonsor DA, Herrera C, Stålhammar-Carlemalm M, Lyndin M, Turner CE, Soden J, van Strijp JAG, Singer BB, van Sorge NM, Lindahl G, McCarthy AJ. 2023. Human CEACAM1 is targeted by a Streptococcus pyogenes adhesin implicated in puerperal sepsis pathogenesis. Nat Commun 14:2675. doi: 10.1038/s41467-023-38372-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B105] 105. Hall A. 1998. Rho GTPases and the actin cytoskeleton. Science 279:509–514. doi: 10.1126/science.279.5350.509 [DOI] [PubMed] [Google Scholar]

[B106] 106. Mishima W, Suzuki A, Yamaji S, Yoshimi R, Ueda A, Kaneko T, Tanaka J, Miwa Y, Ohno S, Ishigatsubo Y. 2004. The first CH domain of affixin activates Cdc42 and Rac1 through αPIX, a Cdc42/Rac1-specific guanine nucleotide exchanging factor. Genes Cells 9:193–204. doi: 10.1111/j.1356-9597.2004.00717.x [DOI] [PubMed] [Google Scholar]

[B107] 107. Moss J, Vaughan M. 1988. ADP-ribosylation of guanyl nucleotide-binding regulatory proteins by bacterial toxins. Adv Enzymol Relat Areas Mol Biol 61:303–379. doi: 10.1002/9780470123072.ch6 [DOI] [PubMed] [Google Scholar]

[B108] 108. Nerlich A, Rohde M, Talay SR, Genth H, Just I, Chhatwal GS. 2009. Invasion of endothelial cells by tissue-invasive M3 type group A streptococci requires Src kinase and activation of Rac1 by a phosphatidylinositol 3-kinase-independent mechanism. J Biol Chem 284:20319–20328. doi: 10.1074/jbc.M109.016501 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B109] 109. Ozeri V, Rosenshine I, Ben-Ze’Ev A, Bokoch GM, Jou TS, Hanski E. 2001. De novo formation of focal complex-like structures in host cells by invading streptococci. Mol Microbiol 41:561–573. doi: 10.1046/j.1365-2958.2001.02535.x [DOI] [PubMed] [Google Scholar]

[B110] 110. Hannigan GE, Leung-Hagesteijn C, Fitz-Gibbon L, Coppolino MG, Radeva G, Filmus J, Bell JC, Dedhar S. 1996. Regulation of cell adhesion and anchorage-dependent growth by a new β1-integrin-linked protein kinase. Nature 379:91–96. doi: 10.1038/379091a0 [DOI] [PubMed] [Google Scholar]

[B111] 111. Persad S, Attwell S, Gray V, Mawji N, Deng JT, Leung D, Yan J, Sanghera J, Walsh MP, Dedhar S. 2001. Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343. J Biol Chem 276:27462–27469. doi: 10.1074/jbc.M102940200 [DOI] [PubMed] [Google Scholar]

[B112] 112. Purushothaman SS, Wang B, Cleary PP. 2003. M1 protein triggers a phosphoinositide cascade for group A Streptococcus invasion of epithelial cells. Infect Immun 71:5823–5830. doi: 10.1128/IAI.71.10.5823-5830.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B113] 113. Nikolopoulos SN, Turner CE. 2001. Integrin-linked kinase (ILK) binding to paxillin LD1 motif regulates ILK localization to focal adhesions. J Biol Chem 276:23499–23505. doi: 10.1074/jbc.M102163200 [DOI] [PubMed] [Google Scholar]

[B114] 114. Wang B, Li S, Dedhar S, Cleary PP. 2007. Paxillin phosphorylation: bifurcation point downstream of integrin-linked kinase (ILK) in streptococcal invasion. Cell Microbiol 9:1519–1528. doi: 10.1111/j.1462-5822.2007.00889.x [DOI] [PubMed] [Google Scholar]

[B115] 115. Kasper KJ, Zeppa JJ, Wakabayashi AT, Xu SX, Mazzuca DM, Welch I, Baroja ML, Kotb M, Cairns E, Cleary PP, Haeryfar SMM, McCormick JK. 2014. Bacterial superantigens promote acute nasopharyngeal infection by Streptococcus pyogenes in a human MHC class II-dependent manner. PLoS Pathog 10:e1004155. doi: 10.1371/journal.ppat.1004155 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B116] 116. Klenk M, Koczan D, Guthke R, Nakata M, Thiesen HJ, Podbielski A, Kreikemeyer B. 2005. Global epithelial cell transcriptional responses reveal Streptococcus pyogenes Fas regulator activity association with bacterial aggressiveness. Cell Microbiol 7:1237–1250. doi: 10.1111/j.1462-5822.2005.00548.x [DOI] [PubMed] [Google Scholar]

[B117] 117. Soderholm AT, Barnett TC, Sweet MJ, Walker MJ. 2018. Group A streptococcal pharyngitis: immune responses involved in bacterial clearance and GAS-associated immunopathologies. J Leukoc Biol 103:193–213. doi: 10.1189/jlb.4MR0617-227RR [DOI] [PubMed] [Google Scholar]

[B118] 118. Tsai PJ, Chen YH, Hsueh CH, Hsieh HC, Liu YH, Wu JJ, Tsou CC. 2006. Streptococcus pyogenes induces epithelial inflammatory responses through NF-κB/MAPK signaling pathways. Microbes Infect 8:1440–1449. doi: 10.1016/j.micinf.2006.01.002 [DOI] [PubMed] [Google Scholar]

[B119] 119. Wang B, Dileepan T, Briscoe S, Hyland KA, Kang J, Khoruts A, Cleary PP. 2010. Induction of TGF-β1 and TGF-β1-dependent predominant Th17 differentiation by group A streptococcal infection. Proc Natl Acad Sci U S A 107:5937–5942. doi: 10.1073/pnas.0904831107 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B120] 120. Gaffen SL, Jain R, Garg AV, Cua DJ. 2014. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat Rev Immunol 14:585–600. doi: 10.1038/nri3707 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B121] 121. Gordon S. 2016. Phagocytosis: an immunobiologic process. Immunity 44:463–475. doi: 10.1016/j.immuni.2016.02.026 [DOI] [PubMed] [Google Scholar]

[B122] 122. Rabinovitch M. 1995. Professional and non-professional phagocytes: an introduction. Trends Cell Biol 5:85–87. doi: 10.1016/s0962-8924(00)88955-2 [DOI] [PubMed] [Google Scholar]

[B123] 123. Zhu H, Liu M, Sumby P, Lei B. 2009. The secreted esterase of group A Streptococcus is important for invasive skin infection and dissemination in mice. Infect Immun 77:5225–5232. doi: 10.1128/IAI.00636-09 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B124] 124. Liu M, Zhu H, Li J, Garcia CC, Feng W, Kirpotina LN, Hilmer J, Tavares LP, Layton AW, Quinn MT, Bothner B, Teixeira MM, Lei B. 2012. Group A Streptococcus secreted esterase hydrolyzes platelet-activating factor to impede neutrophil recruitment and facilitate innate immune evasion. PLoS Pathog 8:e1002624. doi: 10.1371/journal.ppat.1002624 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B125] 125. Edwards RJ, Taylor GW, Ferguson M, Murray S, Rendell N, Wrigley A, Bai Z, Boyle J, Finney SJ, Jones A, Russell HH, Turner C, Cohen J, Faulkner L, Sriskandan S. 2005. Specific C-terminal cleavage and inactivation of interleukin-8 by invasive disease isolates of Streptococcus pyogenes. J Infect Dis 192:783–790. doi: 10.1086/432485 [DOI] [PubMed] [Google Scholar]

[B126] 126. Middleton J, Neil S, Wintle J, Clark-Lewis I, Moore H, Lam C, Auer M, Hub E, Rot A. 1997. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91:385–395. doi: 10.1016/s0092-8674(00)80422-5 [DOI] [PubMed] [Google Scholar]

[B127] 127. Zinkernagel AS, Timmer AM, Pence MA, Locke JB, Buchanan JT, Turner CE, Mishalian I, Sriskandan S, Hanski E, Nizet V. 2008. The IL-8 protease SpyCEP/ScpC of group A Streptococcus promotes resistance to neutrophil killing. Cell Host Microbe 4:170–178. doi: 10.1016/j.chom.2008.07.002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B128] 128. Nozawa T, Iibushi J, Toh H, Minowa-Nozawa A, Murase K, Aikawa C, Nakagawa I. 2021. Intracellular group A Streptococcus induces Golgi fragmentation to impair host defenses through streptolysin O and NAD-glycohydrolase. mBio 12:e01974-20. doi: 10.1128/mBio.01974-20 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B129] 129. Imai T, Matsumura T, Mayer-Lambertz S, Wells CA, Ishikawa E, Butcher SK, Barnett TC, Walker MJ, Imamura A, Ishida H, Ikebe T, Miyamoto T, Ato M, Ohga S, Lepenies B, van Sorge NM, Yamasaki S. 2018. Lipoteichoic acid anchor triggers mincle to drive protective immunity against invasive group A Streptococcus infection. Proc Natl Acad Sci U S A 115:E10662–E10671. doi: 10.1073/pnas.1809100115 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B130] 130. Moses AE, Wessels MR, Zalcman K, Albertí S, Natanson-Yaron S, Menes T, Hanski E. 1997. Relative contributions of hyaluronic acid capsule and M protein to virulence in a mucoid strain of the group A Streptococcus. Infect Immun 65:64–71. doi: 10.1128/iai.65.1.64-71.1997 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B131] 131. Spencer RC. 1995. Invasive streptococci. Eur J Clin Microbiol Infect Dis 14:S26–S32. [PubMed] [Google Scholar]

[B132] 132. Dinkla K, Rohde M, Jansen WTM, Carapetis JR, Chhatwal GS, Talay SR. 2003. Streptococcus pyogenes recruits collagen via surface-bound fibronectin: a novel colonization and immune evasion mechanism. Mol Microbiol 47:861–869. doi: 10.1046/j.1365-2958.2003.03352.x [DOI] [PubMed] [Google Scholar]

[B133] 133. Lembke C, Podbielski A, Hidalgo-Grass C, Jonas L, Hanski E, Kreikemeyer B. 2006. Characterization of biofilm formation by clinically relevant serotypes of group A streptococci. Appl Environ Microbiol 72:2864–2875. doi: 10.1128/AEM.72.4.2864-2875.2006 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B134] 134. Underhill DM, Goodridge HS. 2012. Information processing during phagocytosis. Nat Rev Immunol 12:492–502. doi: 10.1038/nri3244 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B135] 135. Sandin C, Carlsson F, Lindahl G. 2006. Binding of human plasma proteins to Streptococcus pyogenes M protein determines the location of opsonic and non-opsonic epitopes. Mol Microbiol 59:20–30. doi: 10.1111/j.1365-2958.2005.04913.x [DOI] [PubMed] [Google Scholar]

[B136] 136. Hoe NP, Ireland RM, DeLeo FR, Gowen BB, Dorward DW, Voyich JM, Liu M, Burns EH, Culnan DM, Bretscher A, Musser JM. 2002. Insight into the molecular basis of pathogen abundance: group A Streptococcus inhibitor of complement inhibits bacterial adherence and internalization into human cells. Proc Natl Acad Sci U S A 99:7646–7651. doi: 10.1073/pnas.112039899 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B137] 137. Coye LH, Collins CM. 2004. Identification of SpyA, a novel ADP-ribosyltransferase of Streptococcus pyogenes. Mol Microbiol 54:89–98. doi: 10.1111/j.1365-2958.2004.04262.x [DOI] [PubMed] [Google Scholar]

[B138] 138. Hoff JS, DeWald M, Moseley SL, Collins CM, Voyich JM. 2011. SpyA, a C3-like ADP-ribosyltransferase, contributes to virulence in a mouse subcutaneous model of Streptococcus pyogenes infection. Infect Immun 79:2404–2411. doi: 10.1128/IAI.01191-10 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B139] 139. Korotkova N, Hoff JS, Becker DM, Quinn JKH, Icenogle LM, Moseley SL. 2012. SpyA is a membrane-bound ADP-ribosyltransferase of Streptococcus pyogenes which modifies a streptococcal peptide, SpyB. Mol Microbiol 83:936–952. doi: 10.1111/j.1365-2958.2012.07979.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[B140] 140. Datta V, Myskowski SM, Kwinn LA, Chiem DN, Varki N, Kansal RG, Kotb M, Nizet V. 2005. Mutational analysis of the group A streptococcal operon encoding streptolysin S and its virulence role in invasive infection. Mol Microbiol 56:681–695. doi: 10.1111/j.1365-2958.2005.04583.x [DOI] [PubMed] [Google Scholar]

[B141] 141. Feil SC, Ascher DB, Kuiper MJ, Tweten RK, Parker MW. 2014. Structural studies of Streptococcus pyogenes streptolysin O provide insights into the early steps of membrane penetration. J Mol Biol 426:785–792. doi: 10.1016/j.jmb.2013.11.020 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B142] 142. Sierig G, Cywes C, Wessels MR, Ashbaugh CD. 2003. Cytotoxic effects of streptolysin O and streptolysin S enhance the virulence of poorly encapsulated group A streptococci. Infect Immun 71:446–455. doi: 10.1128/IAI.71.1.446-455.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B143] 143. Herwald H, Cramer H, Mörgelin M, Russell W, Sollenberg U, Norrby-Teglund A, Flodgaard H, Lindbom L, Björck L. 2004. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell 116:367–379. doi: 10.1016/s0092-8674(04)00057-1 [DOI] [PubMed] [Google Scholar]

[B144] 144. Macheboeuf P, Buffalo C, Fu CY, Zinkernagel AS, Cole JN, Johnson JE, Nizet V, Ghosh P. 2011. Streptococcal M1 protein constructs a pathological host fibrinogen network. Nature 472:64–68. doi: 10.1038/nature09967 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B145] 145. Håkansson A, Bentley CC, Shakhnovic EA, Wessels MR. 2005. Cytolysin-dependent evasion of lysosomal killing. Proc Natl Acad Sci U S A 102:5192–5197. doi: 10.1073/pnas.0408721102 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B146] 146. Michos A, Gryllos I, Håkansson A, Srivastava A, Kokkotou E, Wessels MR. 2006. Enhancement of streptolysin O activity and intrinsic cytotoxic effects of the group A streptococcal toxin, NAD-glycohydrolase. J Biol Chem 281:8216–8223. doi: 10.1074/jbc.M511674200 [DOI] [PubMed] [Google Scholar]

[B147] 147. Harder J, Franchi L, Muñoz-Planillo R, Park JH, Reimer T, Núñez G. 2009. Activation of the Nlrp3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-κB activation but proceeds independently of TLR signaling and P2X7 receptor. J Immunol 183:5823–5829. doi: 10.4049/jimmunol.0900444 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B148] 148. Keyel PA, Roth R, Yokoyama WM, Heuser JE, Salter RD. 2013. Reduction of streptolysin O (SLO) pore-forming activity enhances inflammasome activation. Toxins (Basel) 5:1105–1118. doi: 10.3390/toxins5061105 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B149] 149. Lin AE, Beasley FC, Keller N, Hollands A, Urbano R, Troemel ER, Hoffman HM, Nizet V. 2015. A group A Streptococcus ADP-ribosyltransferase toxin stimulates a protective interleukin 1β-dependent macrophage immune response. mBio 6:e00133. doi: 10.1128/mBio.00133-15 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B150] 150. Deng W, Bai Y, Deng F, Pan Y, Mei S, Zheng Z, Min R, Wu Z, Li W, Miao R, Zhang Z, Kupper TS, Lieberman J, Liu X. 2022. Streptococcal pyrogenic exotoxin B cleaves GSDMA and triggers pyroptosis. Nature 608:496–502. doi: 10.1038/s41586-022-05109-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[B151] 151. LaRock DL, Johnson AF, Wilde S, Sands JS, Monteiro MP, LaRock CN. 2022. Group A Streptococcus induces GSDMA-dependent pyroptosis in keratinocytes. Nature 605:527–531. doi: 10.1038/s41586-022-04717-x [DOI] [PMC free article] [PubMed] [Google Scholar]

[B152] 152. Muñoz-Planillo R, Kuffa P, Martínez-Colón G, Smith BL, Rajendiran TM, Núñez G. 2013. K⁺ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38:1142–1153. doi: 10.1016/j.immuni.2013.05.016 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B153] 153. Valderrama JA, Riestra AM, Gao NJ, LaRock CN, Gupta N, Ali SR, Hoffman HM, Ghosh P, Nizet V. 2017. Group A streptococcal M protein activates the NLRP3 inflammasome. Nat Microbiol 2:1425–1434. doi: 10.1038/s41564-017-0005-6 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B154] 154. Timmer AM, Timmer JC, Pence MA, Hsu LC, Ghochani M, Frey TG, Karin M, Salvesen GS, Nizet V. 2009. Streptolysin O promotes group A Streptococcus immune evasion by accelerated macrophage apoptosis. J Biol Chem 284:862–871. doi: 10.1074/jbc.M804632200 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B155] 155. Tamura F, Nakagawa R, Akuta T, Okamoto S, Hamada S, Maeda H, Kawabata S, Akaike T. 2004. Proapoptotic effect of proteolytic activation of matrix metalloproteinases by Streptococcus pyogenes thiol proteinase (Streptococcus pyrogenic exotoxin B). Infect Immun 72:4836–4847. doi: 10.1128/IAI.72.8.4836-4847.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B156] 156. Chiang-Ni C, Wang CH, Tsai PJ, Chuang WJ, Lin YS, Lin MT, Liu CC, Wu JJ. 2006. Streptococcal pyrogenic exotoxin B causes mitochondria damage to polymorphonuclear cells preventing phagocytosis of group A Streptococcus. Med Microbiol Immunol 195:55–63. doi: 10.1007/s00430-005-0001-y [DOI] [PubMed] [Google Scholar]

[B157] 157. Kuo CF, Wu JJ, Tsai PJ, Kao FJ, Lei HY, Lin MT, Lin YS. 1999. Streptococcal pyrogenic exotoxin B induces apoptosis and reduces phagocytic activity in U937 cells. Infect Immun 67:126–130. doi: 10.1128/IAI.67.1.126-130.1999 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B158] 158. Nakagawa I, Nakata M, Kawabata S, Hamada S. 2004. Transcriptome analysis and gene expression profiles of early apoptosis-related genes in Streptococcus pyogenes-infected epithelial cells. Cell Microbiol 6:939–952. doi: 10.1111/j.1462-5822.2004.00412.x [DOI] [PubMed] [Google Scholar]

[B159] 159. Tsai PJ, Kuo CF, Lin KY, Lin YS, Lei HY, Chen FF, Wang JR, Wu JJ. 1998. Effect of group A streptococcal cysteine protease on invasion of epithelial cells. Infect Immun 66:1460–1466. doi: 10.1128/IAI.66.4.1460-1466.1998 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B160] 160. Tsai PJ, Lin YS, Kuo CF, Lei HY, Wu JJ. 1999. Group A Streptococcus induces apoptosis in human epithelial cells. Infect Immun 67:4334–4339. doi: 10.1128/IAI.67.9.4334-4339.1999 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B161] 161. Brozna JP, Hauff NF, Phillips WA, Johnston Jr RB. 1988. Activation of the respiratory burst in macrophages. Phosphorylation specifically associated with Fc receptor-mediated stimulation. J Immunol 141:1642–1647. doi: 10.4049/jimmunol.141.5.1642 [DOI] [PubMed] [Google Scholar]

[B162] 162. Dahlgren C, Karlsson A. 1999. Respiratory burst in human neutrophils. J Immunol Methods 232:3–14. doi: 10.1016/s0022-1759(99)00146-5 [DOI] [PubMed] [Google Scholar]

[B163] 163. Nauseef WM. 2004. Assembly of the phagocyte NADPH oxidase. Histochem Cell Biol 122:277–291. doi: 10.1007/s00418-004-0679-8 [DOI] [PubMed] [Google Scholar]

[B164] 164. Winterbourn CC. 2002. Biological reactivity and biomarkers of the neutrophil oxidant, hypochlorous acid. Toxicology 181–182:223–227. doi: 10.1016/s0300-483x(02)00286-x [DOI] [PubMed] [Google Scholar]

[B165] 165. Glaeser J, Nuss AM, Berghoff BA, Klug G. 2011. Singlet oxygen stress in microorganisms. Adv Microb Physiol 58:141–173. doi: 10.1016/B978-0-12-381043-4.00004-0 [DOI] [PubMed] [Google Scholar]

[B166] 166. Henningham A, Döhrmann S, Nizet V, Cole JN. 2015. Mechanisms of group A Streptococcus resistance to reactive oxygen species. FEMS Microbiol Rev 39:488–508. doi: 10.1093/femsre/fuu009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B167] 167. Cleary PP, Larkin A. 1979. Hyaluronic acid capsule: strategy for oxygen resistance in group A streptococci. J Bacteriol 140:1090–1097. doi: 10.1128/jb.140.3.1090-1097.1979 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B168] 168. Söderberg JJ, Engström P, von Pawel-Rammingen U. 2008. The intrinsic immunoglobulin G endopeptidase activity of streptococcal Mac-2 proteins implies a unique role for the enzymatically impaired Mac-2 protein of M28 serotype strains. Infect Immun 76:2183–2188. doi: 10.1128/IAI.01422-07 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B169] 169. Staali L, Bauer S, Mörgelin M, Björck L, Tapper H. 2006. Streptococcus pyogenes bacteria modulate membrane traffic in human neutrophils and selectively inhibit azurophilic granule fusion with phagosomes. Cell Microbiol 8:690–703. doi: 10.1111/j.1462-5822.2005.00662.x [DOI] [PubMed] [Google Scholar]

[B170] 170. Brenot A, King KY, Caparon MG. 2005. The PerR regulon in peroxide resistance and virulence of Streptococcus pyogenes. Mol Microbiol 55:221–234. doi: 10.1111/j.1365-2958.2004.04370.x [DOI] [PubMed] [Google Scholar]

[B171] 171. Brenot A, King KY, Janowiak B, Griffith O, Caparon MG. 2004. Contribution of glutathione peroxidase to the virulence of Streptococcus pyogenes. Infect Immun 72:408–413. doi: 10.1128/IAI.72.1.408-413.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B172] 172. Gao H, Tiwari MK, Kang YC, Lee JK. 2012. Characterization of H₂O-forming NADH oxidase from Streptococcus pyogenes and its application in L-rare sugar production. Bioorg Med Chem Lett 22:1931–1935. doi: 10.1016/j.bmcl.2012.01.049 [DOI] [PubMed] [Google Scholar]

[B173] 173. Gibson CM, Caparon MG. 1996. Insertional inactivation of Streptococcus pyogenes sod suggests that prtF is regulated in response to a superoxide signal. J Bacteriol 178:4688–4695. doi: 10.1128/jb.178.15.4688-4695.1996 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B174] 174. King KY, Horenstein JA, Caparon MG. 2000. Aerotolerance and peroxide resistance in peroxidase and PerR mutants of Streptococcus pyogenes. J Bacteriol 182:5290–5299. doi: 10.1128/JB.182.19.5290-5299.2000 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B175] 175. Gibson CM, Mallett TC, Claiborne A, Caparon MG. 2000. Contribution of NADH oxidase to aerobic metabolism of Streptococcus pyogenes. J Bacteriol 182:448–455. doi: 10.1128/JB.182.2.448-455.2000 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B176] 176. Rosch JW, Caparon MG. 2005. The ExPortal: an organelle dedicated to the biogenesis of secreted proteins in Streptococcus pyogenes. Mol Microbiol 58:959–968. doi: 10.1111/j.1365-2958.2005.04887.x [DOI] [PubMed] [Google Scholar]

[B177] 177. Toukoki C, Gryllos I. 2013. PolA1, a putative DNA polymerase I, is coexpressed with PerR and contributes to peroxide stress defenses of group A Streptococcus. J Bacteriol 195:717–725. doi: 10.1128/JB.01847-12 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B178] 178. Bates CS, Montañez GE, Woods CR, Vincent RM, Eichenbaum Z. 2003. Identification and characterization of a Streptococcus pyogenes operon involved in binding of hemoproteins and acquisition of iron. Infect Immun 71:1042–1055. doi: 10.1128/IAI.71.3.1042-1055.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B179] 179. Brenot A, Weston BF, Caparon MG. 2007. A PerR-regulated metal transporter (PmtA) is an interface between oxidative stress and metal homeostasis in Streptococcus pyogenes. Mol Microbiol 63:1185–1196. doi: 10.1111/j.1365-2958.2006.05577.x [DOI] [PubMed] [Google Scholar]

[B180] 180. Gryllos I, Grifantini R, Colaprico A, Cary ME, Hakansson A, Carey DW, Suarez-Chavez M, Kalish LA, Mitchell PD, White GL, Wessels MR. 2008. PerR confers phagocytic killing resistance and allows pharyngeal colonization by group A Streptococcus. PLoS Pathog 4:e1000145. doi: 10.1371/journal.ppat.1000145 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B181] 181. Janulczyk R, Ricci S, Björck L. 2003. MtsABC is important for manganese and iron transport, oxidative stress resistance, and virulence of Streptococcus pyogenes. Infect Immun 71:2656–2664. doi: 10.1128/IAI.71.5.2656-2664.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B182] 182. Tsou CC, Chiang-Ni C, Lin YS, Chuang WJ, Lin MT, Liu CC, Wu JJ. 2008. An iron-binding protein, Dpr, decreases hydrogen peroxide stress and protects Streptococcus pyogenes against multiple stresses. Infect Immun 76:4038–4045. doi: 10.1128/IAI.00477-08 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B183] 183. Tsou CC, Chiang-Ni C, Lin YS, Chuang WJ, Lin MT, Liu CC, Wu JJ. 2010. Oxidative stress and metal ions regulate a ferritin-like gene, Dpr, in Streptococcus pyogenes. Int J Med Microbiol 300:259–264. doi: 10.1016/j.ijmm.2009.09.002 [DOI] [PubMed] [Google Scholar]

[B184] 184. Bates CS, Toukoki C, Neely MN, Eichenbaum Z. 2005. Characterization of MtsR, a new metal regulator in group A Streptococcus, involved in iron acquisition and virulence. Infect Immun 73:5743–5753. doi: 10.1128/IAI.73.9.5743-5753.2005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B185] 185. Chaussee MA, Callegari EA, Chaussee MS. 2004. Rgg regulates growth phase-dependent expression of proteins associated with secondary metabolism and stress in Streptococcus pyogenes. J Bacteriol 186:7091–7099. doi: 10.1128/JB.186.21.7091-7099.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B186] 186. Riani C, Standar K, Srimuang S, Lembke C, Kreikemeyer B, Podbielski A. 2007. Transcriptome analyses extend understanding of Streptococcus pyogenes regulatory mechanisms and behavior toward immunomodulatory substances. Int J Med Microbiol 297:513–523. doi: 10.1016/j.ijmm.2007.04.005 [DOI] [PubMed] [Google Scholar]

[B187] 187. Ricci S, Janulczyk R, Björck L. 2002. The regulator PerR is involved in oxidative stress response and iron homeostasis and is necessary for full virulence of Streptococcus pyogenes. Infect Immun 70:4968–4976. doi: 10.1128/IAI.70.9.4968-4976.2002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B188] 188. Voyich JM, Braughton KR, Sturdevant DE, Vuong C, Kobayashi SD, Porcella SF, Otto M, Musser JM, DeLeo FR. 2004. Engagement of the pathogen survival response used by group A Streptococcus to avert destruction by innate host defense. J Immunol 173:1194–1201. doi: 10.4049/jimmunol.173.2.1194 [DOI] [PubMed] [Google Scholar]

[B189] 189. Voyich JM, Sturdevant DE, Braughton KR, Kobayashi SD, Lei B, Virtaneva K, Dorward DW, Musser JM, DeLeo FR. 2003. Genome-wide protective response used by group A Streptococcus to evade destruction by human polymorphonuclear leukocytes. Proc Natl Acad Sci U S A 100:1996–2001. doi: 10.1073/pnas.0337370100 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B190] 190. Döhrmann S, Anik S, Olson J, Anderson EL, Etesami N, No H, Snipper J, Nizet V, Okumura CYM. 2014. Role for streptococcal collagen-like protein 1 in M1T1 group A Streptococcus resistance to neutrophil extracellular traps. Infect Immun 82:4011–4020. doi: 10.1128/IAI.01921-14 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B191] 191. Harlan JM, Levine JD, Callahan KS, Schwartz BR, Harker LA. 1984. Glutathione redox cycle protects cultured endothelial cells against lysis by extracellularly generated hydrogen peroxide. J Clin Invest 73:706–713. doi: 10.1172/JCI111263 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B192] 192. Brouwer S, Jespersen MG, Ong CLY, De Oliveira DMP, Keller B, Cork AJ, Djoko KY, Davies MR, Walker MJ. 2022. Streptococcus pyogenes hijacks host glutathione for growth and innate immune evasion. mBio 13:e0067622. doi: 10.1128/mbio.00676-22 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B193] 193. Cederlund A, Gudmundsson GH, Agerberth B. 2011. Antimicrobial peptides important in innate immunity. FEBS J 278:3942–3951. doi: 10.1111/j.1742-4658.2011.08302.x [DOI] [PubMed] [Google Scholar]

[B194] 194. Ganz T. 2004. Antimicrobial polypeptides. J Leukoc Biol 75:34–38. doi: 10.1189/jlb.0403150 [DOI] [PubMed] [Google Scholar]

[B195] 195. Kristian SA, Datta V, Weidenmaier C, Kansal R, Fedtke I, Peschel A, Gallo RL, Nizet V. 2005. D-alanylation of teichoic acids promotes group A Streptococcus antimicrobial peptide resistance, neutrophil survival, and epithelial cell invasion. J Bacteriol 187:6719–6725. doi: 10.1128/JB.187.19.6719-6725.2005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B196] 196. Cole JN, Pence MA, von Köckritz-Blickwede M, Hollands A, Gallo RL, Walker MJ, Nizet V. 2010. M protein and hyaluronic acid capsule are essential for in vivo selection of covRS mutations characteristic of invasive serotype M1T1 group A Streptococcus. mBio 1:e00191-10. doi: 10.1128/mBio.00191-10 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B197] 197. LaRock CN, Döhrmann S, Todd J, Corriden R, Olson J, Johannssen T, Lepenies B, Gallo RL, Ghosh P, Nizet V. 2015. Group A streptococcal M1 protein sequesters cathelicidin to evade innate immune killing. Cell Host Microbe 18:471–477. doi: 10.1016/j.chom.2015.09.004 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B198] 198. Lauth X, von Köckritz-Blickwede M, McNamara CW, Myskowski S, Zinkernagel AS, Beall B, Ghosh P, Gallo RL, Nizet V. 2009. M1 protein allows group A streptococcal survival in phagocyte extracellular traps through cathelicidin inhibition. J Innate Immun 1:202–214. doi: 10.1159/000203645 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B199] 199. Pence MA, Rooijakkers SHM, Cogen AL, Cole JN, Hollands A, Gallo RL, Nizet V. 2010. Streptococcal inhibitor of complement promotes innate immune resistance phenotypes of invasive M1T1 group A Streptococcus. J Innate Immun 2:587–595. doi: 10.1159/000317672 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B200] 200. Hollands A, Gonzalez D, Leire E, Donald C, Gallo RL, Sanderson-Smith M, Dorrestein PC, Nizet V. 2012. A bacterial pathogen co-opts host plasmin to resist killing by cathelicidin antimicrobial peptides. J Biol Chem 287:40891–40897. doi: 10.1074/jbc.M112.404582 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B201] 201. Johansson L, Thulin P, Sendi P, Hertzén E, Linder A, Akesson P, Low DE, Agerberth B, Norrby-Teglund A. 2008. Cathelicidin LL-37 in severe Streptococcus pyogenes soft tissue infections in humans. Infect Immun 76:3399–3404. doi: 10.1128/IAI.01392-07 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B202] 202. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. 2004. Neutrophil extracellular traps kill bacteria. Science 303:1532–1535. doi: 10.1126/science.1092385 [DOI] [PubMed] [Google Scholar]

[B203] 203. Fuchs TA, Abed U, Goosmann C, Hurwitz R, Schulze I, Wahn V, Weinrauch Y, Brinkmann V, Zychlinsky A. 2007. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176:231–241. doi: 10.1083/jcb.200606027 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B204] 204. Khan MA, Palaniyar N. 2017. Transcriptional firing helps to drive NETosis. Sci Rep 7:41749. doi: 10.1038/srep41749 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B205] 205. Steinberg BE, Grinstein S. 2007. Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death. Sci STKE 2007:e11. doi: 10.1126/stke.3792007pe11 [DOI] [PubMed] [Google Scholar]

[B206] 206. Buchanan JT, Simpson AJ, Aziz RK, Liu GY, Kristian SA, Kotb M, Feramisco J, Nizet V. 2006. DNase expression allows the pathogen group A Streptococcus to escape killing in neutrophil extracellular traps. Curr Biol 16:396–400. doi: 10.1016/j.cub.2005.12.039 [DOI] [PubMed] [Google Scholar]

[B207] 207. Döhrmann S, LaRock CN, Anderson EL, Cole JN, Ryali B, Stewart C, Nonejuie P, Pogliano J, Corriden R, Ghosh P, Nizet V. 2017. Group A streptococcal M1 protein provides resistance against the antimicrobial activity of histones. Sci Rep 7:43039. doi: 10.1038/srep43039 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B208] 208. Mayadas TN, Cullere X, Lowell CA. 2014. The multifaceted functions of neutrophils. Annu Rev Pathol 9:181–218. doi: 10.1146/annurev-pathol-020712-164023 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B209] 209. Pinheiro da Silva F, Machado MCC. 2012. Antimicrobial peptides: clinical relevance and therapeutic implications. Peptides 36:308–314. doi: 10.1016/j.peptides.2012.05.014 [DOI] [PubMed] [Google Scholar]

[B210] 210. Winterbourn CC, Metodiewa D. 1999. Reactivity of biologically important thiol compounds with superoxide and hydrogen peroxide. Free Radic Biol Med 27:322–328. doi: 10.1016/s0891-5849(99)00051-9 [DOI] [PubMed] [Google Scholar]

[B211] 211. Kimmey JM, Stallings CL. 2016. Bacterial pathogens versus autophagy: implications for therapeutic interventions. Trends Mol Med 22:1060–1076. doi: 10.1016/j.molmed.2016.10.008 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B212] 212. Siqueira MDS, Ribeiro RDM, Travassos LH. 2018. Autophagy and its interaction with intracellular bacterial pathogens. Front Immunol 9:935. doi: 10.3389/fimmu.2018.00935 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B213] 213. Zhao YG, Codogno P, Zhang H. 2021. Machinery, regulation and pathophysiological implications of autophagosome maturation. Nat Rev Mol Cell Biol 22:733–750. doi: 10.1038/s41580-021-00392-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B214] 214. Zhao YG, Zhang H. 2019. Autophagosome maturation: an epic journey from the ER to lysosomes. J Cell Biol 218:757–770. doi: 10.1083/jcb.201810099 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B215] 215. Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S, Yoshimori T. 2004. Autophagy defends cells against invading group A Streptococcus. Science 306:1037–1040. doi: 10.1126/science.1103966 [DOI] [PubMed] [Google Scholar]

[B216] 216. Yamaguchi H, Nakagawa I, Yamamoto A, Amano A, Noda T, Yoshimori T. 2009. An initial step of GAS-containing autophagosome-like vacuoles formation requires Rab7. PLoS Pathog 5:e1000670. doi: 10.1371/journal.ppat.1000670 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B217] 217. Nozawa T, Aikawa C, Goda A, Maruyama F, Hamada S, Nakagawa I. 2012. The small GTPases Rab9A and Rab23 function at distinct steps in autophagy during group A Streptococcus infection. Cell Microbiol 14:1149–1165. doi: 10.1111/j.1462-5822.2012.01792.x [DOI] [PubMed] [Google Scholar]

[B218] 218. Sakurai A, Maruyama F, Funao J, Nozawa T, Aikawa C, Okahashi N, Shintani S, Hamada S, Ooshima T, Nakagawa I. 2010. Specific behavior of intracellular Streptococcus pyogenes that has undergone autophagic degradation is associated with bacterial streptolysin O and host small G proteins Rab5 and Rab7. J Biol Chem 285:22666–22675. doi: 10.1074/jbc.M109.100131 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B219] 219. Joubert PE, Meiffren G, Grégoire IP, Pontini G, Richetta C, Flacher M, Azocar O, Vidalain PO, Vidal M, Lotteau V, Codogno P, Rabourdin-Combe C, Faure M. 2009. Autophagy induction by the pathogen receptor CD46. Cell Host Microbe 6:354–366. doi: 10.1016/j.chom.2009.09.006 [DOI] [PubMed] [Google Scholar]

[B220] 220. Wang J, Meng M, Li M, Guan X, Liu J, Gao X, Sun Q, Li J, Ma C, Wei L. 2020. Integrin α5β1, as a receptor of fibronectin, binds the FbaA protein of group A Streptococcus to initiate autophagy during infection. mBio 11:e00771-20. doi: 10.1128/mBio.00771-20 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B221] 221. Haobam B, Nozawa T, Minowa-Nozawa A, Tanaka M, Oda S, Watanabe T, Aikawa C, Maruyama F, Nakagawa I. 2014. Rab17-mediated recycling endosomes contribute to autophagosome formation in response to group A Streptococcus invasion. Cell Microbiol 16:1806–1821. doi: 10.1111/cmi.12329 [DOI] [PubMed] [Google Scholar]

[B222] 222. Nozawa T, Aikawa C, Minowa-Nozawa A, Nakagawa I. 2017. The intracellular microbial sensor NLRP4 directs Rho-actin signaling to facilitate group A Streptococcus-containing autophagosome-like vacuole formation. Autophagy 13:1841–1854. doi: 10.1080/15548627.2017.1358343 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B223] 223. Nozawa T, Minowa-Nozawa A, Aikawa C, Nakagawa I. 2017. The STX6-VTI1B-VAMP3 complex facilitates xenophagy by regulating the fusion between recycling endosomes and autophagosomes. Autophagy 13:57–69. doi: 10.1080/15548627.2016.1241924 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B224] 224. Ito C, Saito Y, Nozawa T, Fujii S, Sawa T, Inoue H, Matsunaga T, Khan S, Akashi S, Hashimoto R, Aikawa C, Takahashi E, Sagara H, Komatsu M, Tanaka K, Akaike T, Nakagawa I, Arimoto H. 2013. Endogenous nitrated nucleotide is a key mediator of autophagy and innate defense against bacteria. Mol Cell 52:794–804. doi: 10.1016/j.molcel.2013.10.024 [DOI] [PubMed] [Google Scholar]

[B225] 225. O’Seaghdha M, Wessels MR. 2013. Streptolysin O and its co-toxin NAD-glycohydrolase protect group A Streptococcus from Xenophagic killing. PLoS Pathog 9:e1003394. doi: 10.1371/journal.ppat.1003394 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B226] 226. Lin CY, Nozawa T, Minowa-Nozawa A, Toh H, Hikichi M, Iibushi J, Nakagawa I. 2020. Autophagy receptor Tollip facilitates bacterial autophagy by recruiting galectin-7 in response to group A Streptococcus infection. Front Cell Infect Microbiol 10:583137. doi: 10.3389/fcimb.2020.583137 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B227] 227. Nozawa T, Sano S, Minowa-Nozawa A, Toh H, Nakajima S, Murase K, Aikawa C, Nakagawa I. 2020. TBC1D9 regulates TBK1 activation through Ca²⁺ signaling in selective autophagy. Nat Commun 11:770. doi: 10.1038/s41467-020-14533-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B228] 228. Hikichi M, Toh H, Minowa-Nozawa A, Nozawa T, Nakagawa I. 2022. Guanylate-binding protein 1 regulates infection-induced autophagy through TBK1 phosphorylation. Cell Microbiol 2022:1–18. doi: 10.1155/2022/8612113 [DOI] [Google Scholar]

[B229] 229. Furuta N, Fujita N, Noda T, Yoshimori T, Amano A. 2010. Combinational soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins VAMP8 and Vti1B mediate fusion of antimicrobial and canonical autophagosomes with lysosomes. Mol Biol Cell 21:1001–1010. doi: 10.1091/mbc.e09-08-0693 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B230] 230. Wilkinson DS, Jariwala JS, Anderson E, Mitra K, Meisenhelder J, Chang JT, Ideker T, Hunter T, Nizet V, Dillin A, Hansen M. 2015. Phosphorylation of LC3 by the Hippo kinases STK3/STK4 is essential for autophagy. Mol Cell 57:55–68. doi: 10.1016/j.molcel.2014.11.019 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B231] 231. Nakajima S, Aikawa C, Nozawa T, Minowa-Nozawa A, Toh H, Nakagawa I. 2017. Bcl-xL affects group A Streptococcus-induced autophagy directly, by inhibiting fusion between autophagosomes and lysosomes, and indirectly, by inhibiting bacterial internalization via interaction with Beclin 1-UVRAG. PLoS One 12:e0170138. doi: 10.1371/journal.pone.0170138 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B232] 232. Aikawa C, Nakajima S, Karimine M, Nozawa T, Minowa-Nozawa A, Toh H, Yamada S, Nakagawa I. 2018. NLRX1 negatively regulates group A Streptococcus invasion and autophagy induction by interacting with the Beclin 1-UVRAG complex. Front Cell Infect Microbiol 8:403. doi: 10.3389/fcimb.2018.00403 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B233] 233. Jounai N, Kobiyama K, Shiina M, Ogata K, Ishii KJ, Takeshita F. 2011. NLRP4 negatively regulates autophagic processes through an association with Beclin1. J Immunol 186:1646–1655. doi: 10.4049/jimmunol.1001654 [DOI] [PubMed] [Google Scholar]

[B234] 234. Toh H, Nozawa T, Minowa-Nozawa A, Hikichi M, Nakajima S, Aikawa C, Nakagawa I. 2020. Group A Streptococcus modulates RAB1- and PIK3C3 complex-dependent autophagy. Autophagy 16:334–346. doi: 10.1080/15548627.2019.1628539 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B235] 235. Barnett TC, Liebl D, Seymour LM, Gillen CM, Lim JY, Larock CN, Davies MR, Schulz BL, Nizet V, Teasdale RD, Walker MJ. 2013. The globally disseminated M1T1 clone of group A Streptococcus evades autophagy for intracellular replication. Cell Host Microbe 14:675–682. doi: 10.1016/j.chom.2013.11.003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B236] 236. Bastiat-Sempe B, Love JF, Lomayesva N, Wessels MR. 2014. Streptolysin O and NAD-glycohydrolase prevent phagolysosome acidification and promote group A Streptococcus survival in macrophages. mBio 5:e01690-14. doi: 10.1128/mBio.01690-14 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B237] 237. O’Neill AM, Thurston TLM, Holden DW. 2016. Cytosolic replication of group A Streptococcus in human macrophages. mBio 7:e00931-16. doi: 10.1128/mBio.00931-16 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B238] 238. Sharma O, O’Seaghdha M, Velarde JJ, Wessels MR. 2016. NAD⁺-glycohydrolase promotes intracellular survival of group A Streptococcus. PLoS Pathog 12:e1005468. doi: 10.1371/journal.ppat.1005468 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B239] 239. Lu SL, Kuo CF, Chen HW, Yang YS, Liu CC, Anderson R, Wu JJ, Lin YS. 2015. Insufficient acidification of autophagosomes facilitates group A Streptococcus survival and growth in endothelial cells. mBio 6:e01435-15. doi: 10.1128/mBio.01435-15 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B240] 240. Lu SL, Kawabata T, Cheng YL, Omori H, Hamasaki M, Kusaba T, Iwamoto R, Arimoto H, Noda T, Lin YS, Yoshimori T. 2017. Endothelial cells are intrinsically defective in xenophagy of Streptococcus pyogenes. PLoS Pathog 13:e1006444. doi: 10.1371/journal.ppat.1006444 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B241] 241. Cheng YL, Wu YW, Kuo CF, Lu SL, Liu FT, Anderson R, Lin CF, Liu YL, Wang WY, Chen YD, Zheng PX, Wu JJ, Lin YS. 2017. Galectin-3 inhibits galectin-8/Parkin-mediated ubiquitination of group A Streptococcus. mBio 8:e00899-17. doi: 10.1128/mBio.00899-17 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B242] 242. Cheng YL, Kuo CF, Lu SL, Omori H, Wu YN, Hsieh CL, Noda T, Wu SR, Anderson R, Lin CF, Chen CL, Wu JJ, Lin YS. 2019. Group A Streptococcus induces LAPosomes via SLO/β1 integrin/NOX2/ROS pathway in endothelial cells that are ineffective in bacterial killing and suppress xenophagy. mBio 10:e02148-19. doi: 10.1128/mBio.02148-19 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B243] 243. Hsieh CL, Hsieh SY, Huang HM, Lu SL, Omori H, Zheng PX, Ho YN, Cheng YL, Lin YS, Chiang-Ni C, Tsai PJ, Wang SY, Liu CC, Noda T, Wu JJ. 2020. Nicotinamide increases intracellular NAD⁺ content to enhance autophagy-mediated group A streptococcal clearance in endothelial cells. Front Microbiol 11:117. doi: 10.3389/fmicb.2020.00117 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B244] 244. Lu SL, Omori H, Zhou Y, Lin YS, Liu CC, Wu JJ, Noda T. 2022. VEGF-mediated augmentation of autophagic and lysosomal activity in endothelial cells defends against intracellular Streptococcus pyogenes. mBio 13:e0123322. doi: 10.1128/mbio.01233-22 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B245] 245. Perrin AJ, Jiang X, Birmingham CL, So NSY, Brumell JH. 2004. Recognition of bacteria in the cytosol of mammalian cells by the ubiquitin system. Curr Biol 14:806–811. doi: 10.1016/j.cub.2004.04.033 [DOI] [PubMed] [Google Scholar]

[B246] 246. Stolz A, Ernst A, Dikic I. 2014. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol 16:495–501. doi: 10.1038/ncb2979 [DOI] [PubMed] [Google Scholar]

[B247] 247. Thurston TLM, Ryzhakov G, Bloor S, von Muhlinen N, Randow F. 2009. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat Immunol 10:1215–1221. doi: 10.1038/ni.1800 [DOI] [PubMed] [Google Scholar]

[B248] 248. Thurston TLM, Wandel MP, von Muhlinen N, Foeglein A, Randow F. 2012. Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482:414–418. doi: 10.1038/nature10744 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B249] 249. Huett A, Heath RJ, Begun J, Sassi SO, Baxt LA, Vyas JM, Goldberg MB, Xavier RJ. 2012. The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella typhimurium. Cell Host Microbe 12:778–790. doi: 10.1016/j.chom.2012.10.019 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B250] 250. Noad J, von der Malsburg A, Pathe C, Michel MA, Komander D, Randow F. 2017. LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-κB. Nat Microbiol 2:17063. doi: 10.1038/nmicrobiol.2017.63 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B251] 251. Polajnar M, Dietz MS, Heilemann M, Behrends C. 2017. Expanding the host cell ubiquitylation machinery targeting cytosolic Salmonella. EMBO Rep 18:1572–1585. doi: 10.15252/embr.201643851 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B252] 252. Sharma V, Verma S, Seranova E, Sarkar S, Kumar D. 2018. Selective autophagy and xenophagy in infection and disease. Front Cell Dev Biol 6:147. doi: 10.3389/fcell.2018.00147 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B253] 253. Deretic V, Saitoh T, Akira S. 2013. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 13:722–737. doi: 10.1038/nri3532 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B254] 254. Matsumoto G, Wada K, Okuno M, Kurosawa M, Nukina N. 2011. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 44:279–289. doi: 10.1016/j.molcel.2011.07.039 [DOI] [PubMed] [Google Scholar]

[B255] 255. Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P, Zaffagnini G, Wild P, Martens S, Wagner SA, Youle RJ, Dikic I. 2016. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci U S A 113:4039–4044. doi: 10.1073/pnas.1523926113 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B256] 256. Bell SL, Lopez KL, Cox JS, Patrick KL, Watson RO. 2021. Galectin-8 senses phagosomal damage and recruits selective autophagy adapter TAX1BP1 to control Mycobacterium tuberculosis infection in macrophages. mBio 12:e0187120. doi: 10.1128/mBio.01871-20 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B257] 257. Weng IC, Chen HL, Lo TH, Lin WH, Chen HY, Hsu DK, Liu FT. 2018. Cytosolic galectin-3 and -8 regulate antibacterial autophagy through differential recognition of host glycans on damaged phagosomes. Glycobiology 28:392–405. doi: 10.1093/glycob/cwy017 [DOI] [PubMed] [Google Scholar]

[B258] 258. Hancz D, Westerlund E, Valfridsson C, Aemero GM, Bastiat-Sempe B, Orning P, Lien E, Wessels MR, Persson JJ. 2019. Streptolysin O induces the ubiquitination and degradation of pro-IL-1β. J Innate Immun 11:457–468. doi: 10.1159/000496403 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B259] 259. Ktistakis NT, Tooze SA. 2016. Digesting the expanding mechanisms of autophagy. Trends Cell Biol 26:624–635. doi: 10.1016/j.tcb.2016.03.006 [DOI] [PubMed] [Google Scholar]

[B260] 260. Zhao YG, Zhang H. 2018. Formation and maturation of autophagosomes in higher eukaryotes: a social network. Curr Opin Cell Biol 53:29–36. doi: 10.1016/j.ceb.2018.04.003 [DOI] [PubMed] [Google Scholar]

[B261] 261. Jiang P, Nishimura T, Sakamaki Y, Itakura E, Hatta T, Natsume T, Mizushima N. 2014. The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17. Mol Biol Cell 25:1327–1337. doi: 10.1091/mbc.E13-08-0447 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B262] 262. Langemeyer L, Fröhlich F, Ungermann C. 2018. Rab GTPase function in endosome and lysosome biogenesis. Trends Cell Biol 28:957–970. doi: 10.1016/j.tcb.2018.06.007 [DOI] [PubMed] [Google Scholar]

[B263] 263. Heckmann BL, Green DR. 2019. LC3-associated phagocytosis at a glance. J Cell Sci 132:jcs222984. doi: 10.1242/jcs.222984 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B264] 264. Upadhyay S, Philips JA. 2019. LC3-associated phagocytosis: host defense and microbial response. Curr Opin Immunol 60:81–90. doi: 10.1016/j.coi.2019.04.012 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B265] 265. Martinez J, Malireddi RKS, Lu Q, Cunha LD, Pelletier S, Gingras S, Orchard R, Guan JL, Tan H, Peng J, Kanneganti TD, Virgin HW, Green DR. 2015. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat Cell Biol 17:893–906. doi: 10.1038/ncb3192 [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]

[B266] 266. Gluschko A, Herb M, Wiegmann K, Krut O, Neiss WF, Utermöhlen O, Krönke M, Schramm M. 2018. The β2 integrin Mac-1 induces protective LC3-associated phagocytosis of Listeria monocytogenes. Cell Host Microbe 23:324–337. doi: 10.1016/j.chom.2018.01.018 [DOI] [PubMed] [Google Scholar]

[B267] 267. Kim ML, Martin WJ, Minigo G, Keeble JL, Garnham AL, Pacini G, Smyth GK, Speed TP, Carapetis J, Wicks IP. 2018. Dysregulated IL-1β-GM-CSF axis in acute rheumatic fever that is limited by hydroxychloroquine. Circulation 138:2648–2661. doi: 10.1161/CIRCULATIONAHA.118.033891 [DOI] [PubMed] [Google Scholar]

[B268] 268. Norrby-Teglund A, Chatellier S, Low DE, McGeer A, Green K, Kotb M. 2000. Host variation in cytokine responses to superantigens determine the severity of invasive group A streptococcal infection. Eur J Immunol 30:3247–3255. doi: [DOI] [PubMed] [Google Scholar]

[B269] 269. Fitzgerald KA, Kagan JC. 2020. Toll-like receptors and the control of immunity. Cell 180:1044–1066. doi: 10.1016/j.cell.2020.02.041 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B270] 270. Li D, Wu M. 2021. Pattern recognition receptors in health and diseases. Signal Transduct Target Ther 6:291. doi: 10.1038/s41392-021-00687-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B271] 271. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K, Akira S. 1999. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 11:443–451. doi: 10.1016/s1074-7613(00)80119-3 [DOI] [PubMed] [Google Scholar]

[B272] 272. Eigenbrod T, Pelka K, Latz E, Kreikemeyer B, Dalpke AH. 2015. TLR8 senses bacterial RNA in human monocytes and plays a nonredundant role for recognition of Streptococcus pyogenes. J Immunol 195:1092–1099. doi: 10.4049/jimmunol.1403173 [DOI] [PubMed] [Google Scholar]

[B273] 273. Fieber C, Janos M, Koestler T, Gratz N, Li XD, Castiglia V, Aberle M, Sauert M, Wegner M, Alexopoulou L, Kirschning CJ, Chen ZJ, von Haeseler A, Kovarik P. 2015. Innate immune response to Streptococcus pyogenes depends on the combined activation of TLR13 and TLR2. PLoS One 10:e0119727. doi: 10.1371/journal.pone.0119727 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B274] 274. Hafner A, Kolbe U, Freund I, Castiglia V, Kovarik P, Poth T, Herster F, Weigand MA, Weber ANR, Dalpke AH, Eigenbrod T. 2019. Crucial role of nucleic acid sensing via endosomal Toll-like receptors for the defense of Streptococcus pyogenes in vitro and in vivo. Front Immunol 10:198. doi: 10.3389/fimmu.2019.00198 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B275] 275. Zinkernagel AS, Hruz P, Uchiyama S, von Köckritz-Blickwede M, Schuepbach RA, Hayashi T, Carson DA, Nizet V. 2012. Importance of Toll-like receptor 9 in host defense against M1T1 group A Streptococcus infections. J Innate Immun 4:213–218. doi: 10.1159/000329550 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B276] 276. Movert E, Bolarin JS, Valfridsson C, Velarde J, Skrede S, Nekludov M, Hyldegaard O, Arnell P, Svensson M, Norrby-Teglund A, Cho KH, Elhaik E, Wessels MR, Råberg L, Carlsson F. 2023. Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability. Nat Commun 14:4008. doi: 10.1038/s41467-023-39771-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B277] 277. Fieber C, Kovarik P. 2014. Responses of innate immune cells to group A Streptococcus. Front Cell Infect Microbiol 4:140. doi: 10.3389/fcimb.2014.00140 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B278] 278. Gratz N, Hartweger H, Matt U, Kratochvill F, Janos M, Sigel S, Drobits B, Li XD, Knapp S, Kovarik P. 2011. Type I interferon production induced by Streptococcus pyogenes-derived nucleic acids is required for host protection. PLoS Pathog 7:e1001345. doi: 10.1371/journal.ppat.1001345 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B279] 279. Gratz N, Siller M, Schaljo B, Pirzada ZA, Gattermeier I, Vojtek I, Kirschning CJ, Wagner H, Akira S, Charpentier E, Kovarik P. 2008. Group A Streptococcus activates type I interferon production and MyD88-dependent signaling without involvement of TLR2, TLR4, and TLR9. J Biol Chem 283:19879–19887. doi: 10.1074/jbc.M802848200 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B280] 280. Evavold CL, Kagan JC. 2019. Inflammasomes: threat-assessment organelles of the innate immune system. Immunity 51:609–624. doi: 10.1016/j.immuni.2019.08.005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B281] 281. Richter J, Brouwer S, Schroder K, Walker MJ. 2021. Inflammasome activation and IL-1β signalling in group A Streptococcus disease. Cell Microbiol 23:e13373. doi: 10.1111/cmi.13373 [DOI] [PubMed] [Google Scholar]

[B282] 282. Johnson DC, Taabazuing CY, Okondo MC, Chui AJ, Rao SD, Brown FC, Reed C, Peguero E, de Stanchina E, Kentsis A, Bachovchin DA. 2018. DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat Med 24:1151–1156. doi: 10.1038/s41591-018-0082-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[B283] 283. Swanson KV, Deng M, Ting JPY. 2019. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol 19:477–489. doi: 10.1038/s41577-019-0165-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B284] 284. Duncan JA, Bergstralh DT, Wang Y, Willingham SB, Ye Z, Zimmermann AG, Ting JPY. 2007. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci U S A 104:8041–8046. doi: 10.1073/pnas.0611496104 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B285] 285. Hafner-Bratkovič I, Sušjan P, Lainšček D, Tapia-Abellán A, Cerović K, Kadunc L, Angosto-Bazarra D, Pelegrin P, Jerala R. 2018. NLRP3 lacking the leucine-rich repeat domain can be fully activated via the canonical inflammasome pathway. Nat Commun 9:5182. doi: 10.1038/s41467-018-07573-4 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B286] 286. He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J. 2015. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res 25:1285–1298. doi: 10.1038/cr.2015.139 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B287] 287. Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H, Lieberman J. 2016. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535:153–158. doi: 10.1038/nature18629 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B288] 288. Yang J, Liu Z, Xiao TS. 2017. Post-translational regulation of inflammasomes. Cell Mol Immunol 14:65–79. doi: 10.1038/cmi.2016.29 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B289] 289. Zangiabadi S, Abdul-Sater AA. 2022. Regulation of the NLRP3 inflammasome by posttranslational modifications. J Immunol 208:286–292. doi: 10.4049/jimmunol.2100734 [DOI] [PubMed] [Google Scholar]

[B290] 290. Perregaux D, Gabel CA. 1994. Interleukin-1β maturation and release in response to ATP and nigericin. Evidence that potassium depletion mediated by these agents is a necessary and common feature of their activity. J Biol Chem 269:15195–15203. [PubMed] [Google Scholar]

[B291] 291. Surprenant A, Rassendren F, Kawashima E, North RA, Buell G. 1996. The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7). Science 272:735–738. doi: 10.1126/science.272.5262.735 [DOI] [PubMed] [Google Scholar]

[B292] 292. Walev I, Reske K, Palmer M, Valeva A, Bhakdi S. 1995. Potassium-inhibited processing of IL-1β in human monocytes. EMBO J 14:1607–1614. doi: 10.1002/j.1460-2075.1995.tb07149.x [DOI] [PMC free article] [PubMed] [Google Scholar]

[B293] 293. Westerlund E, Valfridsson C, Yi DX, Persson JJ. 2019. The secreted virulence factor NADase of group A Streptococcus inhibits P2X7 receptor-mediated release of IL-1β. Front Immunol 10:1385. doi: 10.3389/fimmu.2019.01385 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B294] 294. Madden JC, Ruiz N, Caparon M. 2001. Cytolysin-mediated translocation (CMT): a functional equivalent of type III secretion in Gram-positive bacteria. Cell 104:143–152. doi: 10.1016/s0092-8674(01)00198-2 [DOI] [PubMed] [Google Scholar]

[B295] 295. Hancz D, Westerlund E, Bastiat-Sempe B, Sharma O, Valfridsson C, Meyer L, Love JF, O’Seaghdha M, Wessels MR, Persson JJ. 2017. Inhibition of inflammasome-dependent interleukin 1β production by streptococcal NAD⁺-glycohydrolase: evidence for extracellular activity. mBio 8:e00756-17. doi: 10.1128/mBio.00756-17 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B296] 296. Richter J, Monteleone MM, Cork AJ, Barnett TC, Nizet V, Brouwer S, Schroder K, Walker MJ. 2021. Streptolysins are the primary inflammasome activators in macrophages during Streptococcus pyogenes infection. Immunol Cell Biol 99:1040–1052. doi: 10.1111/imcb.12499 [DOI] [PubMed] [Google Scholar]

[B297] 297. Chella Krishnan K, Mukundan S, Alagarsamy J, Hur J, Nookala S, Siemens N, Svensson M, Hyldegaard O, Norrby-Teglund A, Kotb M. 2016. Genetic architecture of group A streptococcal necrotizing soft tissue infections in the mouse. PLoS Pathog 12:e1005732. doi: 10.1371/journal.ppat.1005732 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B298] 298. Kapur V, Majesky MW, Li LL, Black RA, Musser JM. 1993. Cleavage of interleukin 1β (IL-1β) precursor to produce active IL-1β by a conserved extracellular cysteine protease from Streptococcus pyogenes. Proc Natl Acad Sci U S A 90:7676–7680. doi: 10.1073/pnas.90.16.7676 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B299] 299. Johnson AF, Sands JS, Trivedi KM, Russell R, LaRock DL, LaRock CN. 2023. Constitutive secretion of pro-IL-18 allows keratinocytes to initiate inflammation during bacterial infection. PLoS Pathog 19:e1011321. doi: 10.1371/journal.ppat.1011321 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B300] 300. LaRock CN, Todd J, LaRock DL, Olson J, O’Donoghue AJ, Robertson AAB, Cooper MA, Hoffman HM, Nizet V. 2016. IL-1β is an innate immune sensor of microbial proteolysis. Sci Immunol 1:eaah3539. doi: 10.1126/sciimmunol.aah3539 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B301] 301. LaRock DL, Russell R, Johnson AF, Wilde S, LaRock CN. 2020. Group A Streptococcus infection of the nasopharynx requires proinflammatory signaling through the interleukin-1 receptor. Infect Immun 88:e00356-20. doi: 10.1128/IAI.00356-20 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B302] 302. Nakagawa I, Nakata M, Kawabata S, Hamada S. 2001. Cytochrome c-mediated caspase-9 activation triggers apoptosis in Streptococcus pyogenes-infected epithelial cells. Cell Microbiol 3:395–405. doi: 10.1046/j.1462-5822.2001.00122.x [DOI] [PubMed] [Google Scholar]

[B303] 303. Jorgensen I, Rayamajhi M, Miao EA. 2017. Programmed cell death as a defence against infection. Nat Rev Immunol 17:151–164. doi: 10.1038/nri.2016.147 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B304] 304. Booty LM, Bryant CE. 2022. Gasdermin D and beyond - gasdermin-mediated pyroptosis in bacterial infections. J Mol Biol 434:167409. doi: 10.1016/j.jmb.2021.167409 [DOI] [PubMed] [Google Scholar]

[B305] 305. Keestra-Gounder AM, Nagao PE. 2023. Inflammasome activation by Gram-positive bacteria: mechanisms of activation and regulation. Front Immunol 14:1075834. doi: 10.3389/fimmu.2023.1075834 [DOI] [PMC free article] [PubMed] [Google Scholar]

[B306] 306. Broz P, Pelegrín P, Shao F. 2020. The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol 20:143–157. doi: 10.1038/s41577-019-0228-2 [DOI] [PubMed] [Google Scholar]

[B307] 307. Liu X, Xia S, Zhang Z, Wu H, Lieberman J. 2021. Channelling inflammation: gasdermins in physiology and disease. Nat Rev Drug Discov 20:384–405. doi: 10.1038/s41573-021-00154-z [DOI] [PMC free article] [PubMed] [Google Scholar]

[B308] 308. Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM. 2015. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666–671. doi: 10.1038/nature15541 [DOI] [PubMed] [Google Scholar]

PERMALINK

Interplay between group A Streptococcus and host innate immune responses

Marcia Shu-Wei Su

Yi-Lin Cheng

Yee-Shin Lin

Jiunn-Jong Wu

Roles

SUMMARY

INTRODUCTION

Fig 1.

ARMS RACE BETWEEN THE HOST COMPLEMENT SYSTEM AND GAS VIRULENCE FACTORS

Fig 2.

Interfering with the recognition of GAS

Preventing the formation of C3 convertase and degrading C3b opsonin

Avoiding C3b opsonization and preventing C5 convertase formation

Degrading C3a and C5a and abolishing recruitment of neutrophils

Resisting MAC formation and MAC-induced lysis

Tampering with human complement regulators

GAS ATTACHMENT, INTERNALIZATION, AND GAS-MEDIATED SIGNALING EVENTS

TABLE 1.

GAS EVADES PHAGOCYTOSIS

The early stage of phagocytosis: GAS circumvents phagocyte recruitment, abolishes antibody-mediated opsonization, and inhibits phagocyte uptake

The middle stage of phagocytosis: GAS kills phagocytic cells

The middle stage of phagocytosis: GAS counteracts host oxidative bursts and ROS-related metal acquisition

The late stage of phagocytosis: GAS resists host anti-microbial killing and escapes from neutrophil extracellular traps

SELECTIVE AUTOPHAGY (XENOPHAGY) AGAINST GAS INFECTION

Fig 3.

TABLE 2.

Xenophagy induction/initiation

Elongation and GcAV expansion

Substrate targeting

Autophagosome maturation and fusion with lysosomes

DEFECTIVE XENOPHAGY AND LC3-ASSOCIATED PHAGOCYTOSIS in GAS-INFECTED ENDOTHELIAL CELLS

Fig 4.

INFLAMMATION AND INFLAMMOSOME ACTIVATION

Inflammation

NLRP3 inflammasome-dependent pathway

NLRP3 inflammasome-independent pathway

CELL DEATH RELATED TO GAS INTERFERENCE

CONCLUDING REMARKS

ACKNOWLEDGMENTS

Biographies

Contributor Information

REFERENCES

ACTIONS

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RESOURCES

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