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Published in final edited form as: Curr Opin Microbiol. 2013 Dec 22;0:61–66. doi: 10.1016/j.mib.2013.11.008

Detection of cytosolic bacteria by inflammatory caspases

Jon A Hagar 1, Edward A Miao 1
PMCID: PMC3942666  NIHMSID: NIHMS551761  PMID: 24581694

Abstract

The sanctity of the cytosolic compartment is rigorously maintained by a number of innate immune mechanisms. Inflammasomes detect signatures of microbial infection and trigger caspase-1 or caspase-11 activation, culminating in cytokine secretion and obliteration of the replicative niche via pyroptosis. Recent studies have examined inflammatory caspase responses to cytosolic bacteria, including Burkholderia, Shigella, Listeria, Francisella, and Mycobacterium species. For example, caspase-11 responds to LPS introduced into the cytosol after Gram-negative bacteria escape the vacuole. Not surprisingly, bacteria antagonize these responses; for example, Shigella delivers OspC3 to inhibit caspase-4. These findings underscore bacterial coevolution with the innate immune system, which has resulted in few, but highly specialized cytosolic pathogens.

INTRODUCTION

The immune defenses of the extracellular environment are severe, as are those of the phagolysosome. The prospect of refuge from these insults therefore makes the cytosolic compartment a theoretically attractive refuge for potential bacterial pathogens. However, the fact that bona fide cytosolic bacteria can be counted on one’s fingers (see Table 1 for a summary of these pathogens, their cell tropisms, and their mechanisms for invading the cytosol) highlights the successful immune defenses employed to maintain the sterility of the cytosolic niche. A number of cytosolic sensors detect signatures of infection, initiating potent inflammatory responses and/or host cell death. The importance of inflammatory caspases in this regard is underscored by the extreme susceptibility of mice deficient in these enzymes to infection by cytosolic pathogens. Interestingly, the few cytosolic specialist pathogens are among the most virulent known. Herein, we discuss the role of inflammatory caspases in the innate immune response to cytosolic bacteria, focusing on recent advances in our understanding of how cells detect intruders and trigger caspase activation, and how caspases mediate containment of the infection.

Table 1.

Cell tropism and vacuolar escape determinants of cytosolic bacteria.

Genus Gram +/− Cell tropism Vacuolar escape determinants, bacterial
Burkholderia Mφ, PMN, epithelial cells T3SSBSA
Shigella Mφ, DC, intestinal epithelial cells Mxi-Spa T3SS, IpaB
Francisella Mφ, PMN, DC, epithelial cells, hepatocytes IglC, MglA, FTT11103
Listeria + Mφ, intestinal epithelial LLO, phospholipase C
Rickettsia Vascular endothelial, Mφ Phospholipases, hemolysin
Mycobacterium Acid-fast + ESX-1 T7SS, ESAT-6

THE INFLAMMATORY CASPASES

Caspases are ancient and evolutionarily conserved proteases that are integral to development, homeostasis, and immunity. Some caspases are involved in apoptosis, an immunologically silent form of programmed cell death. In contrast, the inflammatory caspases, caspase-11 (or the presumed human homologs caspase-4 and caspase-5) and caspase-1, initiate a form of lytic cell death termed pyroptosis following their activation, which releases inflammatory mediators, removes the replicative niche of cytosolic bacteria, and exposes intruders to extracellular defenses and neutrophils [1] (reviewed in [2]). In addition, caspase-1 mediates the maturation and secretion of pro-IL-1β and pro-IL-18, two pleiotropic inflammatory cytokines best known for inducing fever and interferon (IFN)-γ secretion, respectively [3].

THE INFLAMMASOMES

The inflammatory caspases are expressed as inactive zymogens. The canonical inflammasomes, a class of cytosolic pattern recognition receptors (PRR), activate caspase-1 in response to specific signatures of infection. A theorized non-canonical inflammasome(s) is proposed to activate caspase-11 [4]. Relevant inflammasomes and their agonists are detailed in Table 2; for in-depth review, see [2] and [3].

Table 2.

Interaction of inflammatory caspases and cytosolic bacteria.

Bacteria Caspase-1 Caspase-11 or -4
Stimulus/sensor NLRC4 NLRP3 AIM2
Burkholderia BsaK/NAIP2 Infection LPS/casp11
Shigella Needle/NAIP1 and human NAIP
Rod/NAIP2
Infection LPS/casp11 ?/casp4
Francisella Infection (human) DNA
Listeria Flagellin/NAIP5 Infection, LLO DNA
Rickettsia
Mycobacterium Infection, ESAT-6 DNA
Antagonism
Burkholderia
Shigella OspC3 inhibits casp4
Francisella possible Tetra-acyl LPS
Listeria Represses flagellin at host temperatures pH dependent LLO activity
Rickettsia
Mycobacterium Zmp1 metalloprotease

Burkholderia

B. pseudomallei and B. thailandensis have served as models for studying the interaction of inflammatory caspases and cytosolic bacteria. These Gram-negative bacteria exist ubiquitously in the soil of southeast Asia and sporadically elsewhere [5]. Although closely related, only B. pseudomallei causes severe human and murine disease; however, B. thailandensis can infect macrophages and epithelial cells both in vitro and in vivo. B. pseudomallei and B. thailandensis rapidly escape the vacuole via their type III secretion system (T3SS) [6][7]. NLRC4 is positioned to detect signatures of T3SS activity, alerting the immune system to pathogens that reprogram and parasitize host cells. Not surprisingly, we and others found that macrophage infection triggers NLRC4 activation [8][9]. Mediating this activation, we showed that the T3SS rod protein BsaK is detected through NLRC4 [10], and Zhao and colleagues demonstrated that NAIP2 is the sensor upstream of NLRC4 [11]. Later the T3SS needle protein BsaL, as well as needle proteins from a variety of other bacteria, was found to be detected by murine NAIP1 and human NAIP, both signaling through NLRC4 downstream [11][12][13]. By an ill-defined mechanism, Burkholderia species also activate NLRP3 [8][9]. Together, NLRC4 and NLRP3 are critical for mice to resist intranasal B. pseudomallei challenge [8]. In this model, IL-18 is central to this resistance, coordinating bacterial clearance, whereas IL-1β secretion mediates immune pathology driven by neutrophil recruitment.

Recently, we determined that caspase-11 is critical for mice to resist infection by both virulent B. pseudomallei as well as avirulent B. thailandensis [9]. Caspase-11 functions independently of all known inflammasomes, instead working in parallel with caspase-1 to mediate protection against ubiquitous environmental bacteria. We discovered that caspase-11 responds specifically to Gram-negative cytosolic bacteria, where normally vacuolar bacteria such as Legionella pneumophila and Salmonella enterica serovar typhimurium (S. typhimurium) rapidly induce caspase-11 dependent pyroptosis only after aberrant translocation to the cytosol. In complementary studies, we and Kayagaki and colleagues determined that cytoplasmic translocation of penta- and hexa-acylated LPS, but not tetra-acylated LPS, triggers caspase-11 activation [14][15]. Although enhanced by TLR4 signaling, this pathway can proceed independently of extracellular LPS signaling. Thus, Tlr4−/− mice primed with a TLR3 agonist succumb to secondary LPS challenge in a model of endotoxic shock. Previous studies indicate that during prolonged infections, caspase-11 activates in response to all Gram-negative bacteria [4][16][17][18]. We speculate that such activation may reflect vacuole leakage events that accumulate over 16h, which may have relevance in the setting of Gram-negative septic shock. In contrast, caspase-11 rapidly responds to L. pneumophila infection in pre-activated macrophages [19][20]; whether vacuolar integrity is compromised under these conditions remains to be examined. The physiologic role of caspase-11 during infection is to combat cytosolic bacteria. The upstream sensor that detects cytosolic LPS remains unknown.

Shigella

Members of the Gram-negative Shigella genus are exquisitely adapted to cause human gastrointestinal disease. S. flexneri infects a variety of cell types, such as intestinal epithelial cells and macrophages. Following phagocytosis by macrophages or T3SS-mediated uptake by epithelial cells, S. flexneri rapidly escapes the phagosome. In vitro, S. flexneri is robustly detected by caspase-1 via NLRC4 [21] and, under some conditions NLRP3 [22]. As an aflagellate bacterium, S. flexneri does not expressed flagellin. We showed that the MxiI rod protein is detected via NLRC4 [10], and Zhao showed this was via NAIP2 [11]. The S. flexneri needle component MxiH is also detected by murine NAIP1 and human NAIP [12]. As with Burkholderia, NLRC4 is positioned to detect Shigella before cytosolic invasion, and thus does not differentiate it from vacuolar T3SS utilizing bacteria such as S. typhimurium. Whether inflammasome pathways more tailored to detecting cytosolic bacteria (AIM2 or caspase-11) function in resistance to Shigella infection remains to be determined; however, we have found that both S. flexneri infection and transfection of S. flexneri lysates into macrophages activate caspase-11 in vitro (our unpublished observations), indicating that S. flexneri lipid A can be detected by the caspase-11 pathway.

Recently, work employing a Guinea pig model of Shigella infection, which more faithfully models human infection than mouse models, has implicated caspase-4 in host resistance to S. flexneri [23]. Kobayashi and colleagues found that caspase-4 mediates epithelial cell death in response to several enteric pathogens, and that S. flexneri secretes an inhibitor of caspase-4 activation, OspC3, to counteract this innate immune response in vitro and in vivo. Remarkably, the authors found that OspC3 is specific in antagonizing caspase-4 and does not associate with caspase-11, highlighting the specificity of Shigella species for infecting humans. Future research will determine whether caspase-4 responds to cytoplasmic LPS as does caspase-11, which would situate caspase-4 as key preserver of cytosolic sterility.

Francisella

The causative agent of tularemia, Gram-negative F. tularensis is among the most infectious and virulent pathogens; thus, it is classified as a category A bioweapon. F. tularensis infects a variety of cell types, with macrophages and neutrophils representing the primary replicative niches during pneumonic infection [24]. F. novicida is closely related to F. tularensis, but is far less virulent. F. novicida lyses in the cytosol of murine macrophages, releasing DNA that triggers AIM2/ASC/caspase-1 [25][26][27][28][29][30]. In vivo, Aim2-deficient mice have increased susceptibility to F. novicida infection [27][28]. In some experimental systems, F. novicida also triggers NLRP3 activation [31]. However, murine infection by F. tularensis, unlike byF. novicida, results in little detectable caspase-1 activation [32], suggesting virulent strains have evolved to evade AIM2. A better understanding of this difference may have implications for both the treatment of and vaccination against tularemia.

Francisella species express tetra-acylated LPS. Not surprisingly, we have found that macrophages do not activate caspase-11 after infection by F. novicida [15]. However, transfection of penta-acylated lipid A from an lpxF mutant, but not wild-type tetra-acylated lipid A, triggers caspase-11 dependent pyroptosis. Therefore, Francisella species appear to have evolved to evade a major host cytosol surveillance pathway, the non-canonical inflammasome.

Listeria

Listeria monocytogenes is a Gram-positive saprophyte and facultative pathogen that causes self-limited gastroenteritis in immunocompetent individuals. Of particular concern for the immunocompromised, L. monocytogenes infections can progress to cause sepsis, encephalitis, and death; in pregnant mothers, it can trigger abortion. L. monocytogenes readily escapes into the cytosol of epithelial cells and macrophages using the pore-forming toxin listeriolysin O (LLO).

In vitro, macrophages detect cytosolic L. monocytogenes via NLRC4 and AIM2; NLRP3 also detects infection under certain experimental conditions [26][33][34][35][36][37][38], but not others [39][40]. In the absence of infection, the pore-forming activity of purified LLO protein is sufficient to trigger NLRP3 activation [33]. NLRC4 responds to flagellin sloughed from L. monocytogenes in the cytosol. In this case, NLRC4 acts as a specific sensor of cytosolic invasion, whereas it does not differentiate between cytosolic or vacuolar T3SS-expressing bacteria. AIM2 responds to DNA released into the cytosol following infrequent lysis of L. monocytogenes.

In vivo, Casp1−/− Casp11−/− mice may have increased susceptibility to L. monocytogenes infection [41]; however, this was not replicated in another publication [40]. Furthermore, the contributions of individual inflammasomes during in vivo infection are not defined. Nevertheless, L. monocytogenes appears to have evolved to limit inflammasome detection: LLO activity is optimal in the acidic environment of the phagosome, thus limiting its potential to trigger NLRP3; flagellin expression is repressed during growth at host temperature; and few bacteria lyse in the cytosol, thus limiting cytosolic DNA exposure. The efficiency of these evasive strategies is demonstrated by the rapid clearance of L. monocytogenes forced to express flagellin in vivo [40][42].

By virtue of its nature as a Gram-positive bacterium, L. monocytogenes does not contain LPS, and thus is not detected by caspase-11 [15][43].

Rickettsia

Members of the genus Rickettsia are Gram-negative, obligate intracellular pathogens that invade the cytosol of vascular endothelial cells and macrophages, causing a variety of arthropod-borne diseases. Little research to date has investigated the interactions of inflammatory caspases and Rickettsia; however, infected mouse peritoneal macrophages secrete IL-1β [44], suggesting that caspase-1 responds to certain Rickettsia species. Interestingly, IFN-γ primed RAW264.7 macrophage-like cells undergo rapid cell death (within 4h) following infection with R. prowazekii [45]. It is tempting to speculate that the enhanced bactericidal activity of IFN-γ primed macrophages potentiates AIM2 or caspase-11 detection of Rickettsia.

Mycobacterium

Among Mycobacterium species, M. marinum is distinct in that it rapidly escapes the phagosome to replicate in the cytosol and spread cell-to-cell. Vacuolar escape requires ESAT-6, a secretion product of the ESX-1 type VII secretion system suggested to have membrane pore forming activity [46]. Although M. tuberculosis is traditionally considered a vacuolar pathogen of macrophages, recent studies suggest it may exist in the cytosol for at least part of its intracellular life cycle (reviewed in [47]).

A number of studies have investigated the role of inflammatory caspases in immunity to M. tuberculosis and M. marinum. While the in vivo importance of IL-1α and IL-1β are well accepted, the role of NLRP3, ASC, and caspase-1 remain controversial both in vivo and in vitro (for a more in-depth review, see [3]). Herein we limit our discussion to the recent studies examining caspase-1 activation in response to cytosolic bacterial exposure. Several studies implicate ESX-1 and ESAT-6 in caspase-1 activation [48][49][50][51][52][53]. Abdallah and colleagues suggest that ESX-1 translocation of mycobacteria to the cytosol potentiates subsequent ESX-5 dependent inflammasome activation [54]. M. tuberculosis DNA can access the cytosol in a manner dependent on ESX-1, where it triggers STING-dependent type I interferon production [55]. DNA from M. tuberculosis and M. bovis also trigger AIM2/ASC/caspase-1 [56][57], and Aim2−/− mice appear susceptible to M. tuberculosis infection, suggesting a physiologic relevance to the in vitro detection data [56]. A recent contradictory report suggests that virulent M. tuberculosis strains actually inhibit AIM2 activation, whereas nonvirulent strains do not [58]; use of different macrophage types in these studies may reconcile their conflicting findings.

CONCLUSIONS

In recent years, our understanding of inflammatory caspase activation has expanded to include several new sensor-stimulus pairs, such as AIM2 and DNA, NAIP1 and the T3SS needle, and LPS and the non-canonical inflammasome. These findings have elucidated how the inflammatory caspases and, more generally, the innate immune system restrict the ability of pathogens to establish cytosolic growth niches. At the same time, they pose a number of questions, such as the identity of the non-canonical inflammasome. Furthermore, several models of cytosolic pathogen interaction with inflammatory caspases remain under-explored, such as Rickettsia infection and the emerging paradigm of cytosolic M. tuberculosis. Future studies will begin to fill these gaps and, surely, raise a number of new questions.

HIGHLIGHTS.

  • Specific NAIPs activate NLRC4 in response to flagellin and the T3SS rod and needle proteins

  • Caspase-11 defends against Burkholderia species by responding to cytosolic LPS

  • OspC3 translocation by Shigellais a novel mechanism of caspase-4 antagonism

  • Mycobacterium tuberculosis may have a cytosolic phase of its lifecycle that exposes it to cytosolic sensors

Acknowledgments

This work is supported by the National Institute of Health grants AI007273 (JAH), AI097518 (EAM) and AI057141 (EAM). We apologize for any references omitted due to space constraints.

Footnotes

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References

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest

•• of outstanding interest

  • 1.Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, Sarkar A, Warren SE, Wewers MD, Aderem A. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nature immunology. 2010;11:1136–42. doi: 10.1038/ni.1960. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Aachoui Y, Sagulenko V, Miao EA, Stacey KJ. Inflammasome-mediated pyroptotic and apoptotic cell death, and defense against infection. Current opinion in microbiology. 2013;16:319–26. doi: 10.1016/j.mib.2013.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Moltke von J, Ayres JS, Kofoed EM, Chavarría-Smith J, Vance RE. Recognition of bacteria by inflammasomes. Annual review of immunology. 2013;31:73–106. doi: 10.1146/annurev-immunol-032712-095944. [DOI] [PubMed] [Google Scholar]
  • 4••.Kayagaki N, Warming S, Lamkanfi M, Walle LV, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479:117–21. doi: 10.1038/nature10558. Determination that Casp1-deficient mice also are Casp11-deficient, and that certain phenotypes ascribed to caspase-1 are actually the result of caspase-11 activity. [DOI] [PubMed] [Google Scholar]
  • 5.Currie BJ, Dance DA, Cheng AC. The global distribution of Burkholderia pseudomallei and melioidosis: an update. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2008;102 (Suppl 1):S1–4. doi: 10.1016/S0035-9203(08)70002-6. [DOI] [PubMed] [Google Scholar]
  • 6.Adler NR, Govan B, Cullinane M, Harper M, Ben Adler, Boyce JD. The molecular and cellular basis of pathogenesis in melioidosis: how does Burkholderia pseudomallei cause disease? FEMS microbiology reviews. 2009;33:1079–99. doi: 10.1111/j.1574-6976.2009.00189.x. [DOI] [PubMed] [Google Scholar]
  • 7.French CT, Toesca IJ, Wu T, Teslaa T, Beaty SM, Wong W, Liu M, Schröder I, Chiou P, Teitell MA, et al. Dissection of the Burkholderia intracellular life cycle using a photothermal nanoblade. Proceedings of the National Academy of Sciences of the United States of America. 2011;108:12095–100. doi: 10.1073/pnas.1107183108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8•.Ceballos-Olvera I, Sahoo M, Miller MA, del Barrio L, Re F. Inflammasome-dependent pyroptosis and IL-18 protect against Burkholderia pseudomallei lung infection while IL-1β is deleterious. PLoS pathogens. 2011;7:e1002452. doi: 10.1371/journal.ppat.1002452. The authors eloquently describe how inflammasome outputs affect disease in a complex manner depending on disease. In this case, whereas IL-18 and pyroptosis mediate host resistance to pneumonic infection, IL-1β contributes to immune pathology. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9••.Aachoui Y, Leaf IA, Hagar JA, Fontana MF, Campos CG, Zak DE, Tan MH, Cotter PA, Vance RE, Aderem A, et al. Caspase-11 protects against bacteria that escape the vacuole. Science. 2013;339:975–8. doi: 10.1126/science.1230751. This is the first demonstration of protective role for caspase-11 during infection. Previous studies showed only deleterious roles, such as during endotoxic shock. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Miao EA, Mao DP, Yudkovsky N, Bonneau R, Lorang CG, Warren SE, Leaf IA, Aderem A. Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:3076–80. doi: 10.1073/pnas.0913087107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11•.Zhao Y, Yang J, Shi J, Gong Y, Lu Q, Xu H, Liu L, Shao F. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature. 2011;477:596–600. doi: 10.1038/nature10510. The authors provide mechanistic details of NLRC4 inflammasome ligand specificity, providing an explanation of how the inflammasome responds to flagellin and T3SS components. [DOI] [PubMed] [Google Scholar]
  • 12.Yang J, Zhao Y, Shi J, Shao F. Human NAIP and mouse NAIP1 recognize bacterial type III secretion needle protein for inflammasome activation. Proceedings of the National Academy of Sciences of the United States of America. 2013 doi: 10.1073/pnas.1306376110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Rayamajhi M, Zak DE, Chavarría-Smith J, Vance RE, Miao EA. Cutting Edge: Mouse NAIP1 Detects the Type III Secretion System Needle Protein. Journal of immunology. doi: 10.4049/jimmunol.1301549. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14••.Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, Miyake K, Zhang J, Lee WP, Muszynski A, et al. Noncanonical Inflammasome Activation by Intracellular LPS Independent of TLR4. Science. 2013 doi: 10.1126/science.1240248. The authors identify cytoplasmic LPS as the trigger of caspase-11 activation. Furthermore, they demonstrate that caspase-11 can drive endotoxic shock independently of TLR4. [DOI] [PubMed] [Google Scholar]
  • 15••.Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science. 2013 doi: 10.1126/science.1240988. doi:10.1126/science. 1240988. In a complementary study to [14], we also identify cytoplasmic LPS as the trigger of caspase-11 activation and demonstrate that caspase-11 can drive endotoxic shock independently of TLR4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Rathinam VA, Vanaja SK, Waggoner L, Sokolovska A, Becker C, Stuart LM, Leong JM, Fitzgerald KA. TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell. 2012;150:606–19. doi: 10.1016/j.cell.2012.07.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Broz P, Ruby T, Belhocine K, Bouley DM, Kayagaki N, Dixit VM, Monack DM. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature. 2012;490:288–91. doi: 10.1038/nature11419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Gurung P, Malireddi RK, Anand PK, Demon D, Walle LV, Liu Z, Vogel P, Lamkanfi M, Kanneganti T. Toll or interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-β (TRIF)-mediated caspase-11 protease production integrates Toll-like receptor 4 (TLR4) protein- and Nlrp3 inflammasome-mediated host defense against enteropathogens. The Journal of biological chemistry. 2012;287:34474–83. doi: 10.1074/jbc.M112.401406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Casson CN, Copenhaver AM, Zwack EE, Nguyen HT, Strowig T, Javdan B, Bradley WP, Fung TC, Flavell RA, Brodsky IE, et al. Caspase-11 activation in response to bacterial secretion systems that access the host cytosol. PLoS pathogens. 2013;9:e1003400. doi: 10.1371/journal.ppat.1003400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Case CL, Kohler LJ, Lima JB, Strowig T, de Zoete MR, Flavell RA, Zamboni DS, Roy CR. Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:1851–6. doi: 10.1073/pnas.1211521110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y, Mimuro H, Inohara N, Sasakawa C, Nuñez G. Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS pathogens. 2007;3:e111. doi: 10.1371/journal.ppat.0030111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Davis BK, Roberts RA, Huang MT, Willingham SB, Conti BJ, Brickey WJ, Barker BR, Kwan M, Taxman DJ, Accavitti-Loper M, et al. Cutting edge: NLRC5-dependent activation of the inflammasome. Journal of immunology. 2011;186:1333–7. doi: 10.4049/jimmunol.1003111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23••.Kobayashi T, Ogawa M, Sanada T, Mimuro H, Kim M, Ashida H, Akakura R, Yoshida M, Kawalec M, Reichhart J, et al. The Shigella OspC3 effector inhibits caspase-4, antagonizes inflammatory cell death, and promotes epithelial infection. Cell host & microbe. 2013;13:570–83. doi: 10.1016/j.chom.2013.04.012. This is, to our knowledge, the first data to suggest a protective role for caspase-4 during bacterial infection. Furthermore, the authors identify a novel mechanism of inflammatory caspase antagonism employed by pathogenic S. flexneri. [DOI] [PubMed] [Google Scholar]
  • 24.Hall JD, Woolard MD, Gunn BM, Craven RR, Taft-Benz S, Frelinger JA, Kawula TH. Infected-host-cell repertoire and cellular response in the lung following inhalation of Francisella tularensis Schu S4, LVS, or U112. Infection and immunity. 2008;76:5843–52. doi: 10.1128/IAI.01176-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Huang MT, Mortensen BL, Taxman DJ, Craven RR, Taft-Benz S, Kijek TM, Fuller JR, Davis BK, Allen IC, Brickey WJ, et al. Deletion of ripA alleviates suppression of the inflammasome and MAPK by Francisella tularensis. Journal of immunology. 2010;185:5476–85. doi: 10.4049/jimmunol.1002154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L, Vanaja SK, Monks BG, Ganesan S, Latz E, et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature immunology. 2010;11:395–402. doi: 10.1038/ni.1864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Fernandes-Alnemri T, Yu J, Juliana C, Solorzano L, Kang S, Wu J, Datta P, McCormick M, Huang L, McDermott E, et al. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nature immunology. 2010;11:385–93. doi: 10.1038/ni.1859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Jones JW, Kayagaki N, Broz P, Henry T, Newton K, O’Rourke K, Chan S, Dong J, Qu Y, Roose-Girma M, et al. Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:9771–6. doi: 10.1073/pnas.1003738107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Peng K, Broz P, Jones J, Joubert L, Monack D. Elevated AIM2-mediated pyroptosis triggered by hypercytotoxic Francisella mutant strains is attributed to increased intracellular bacteriolysis. Cellular microbiology. 2011;13:1586–600. doi: 10.1111/j.1462-5822.2011.01643.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Pierini R, Juruj C, Perret M, Jones CL, Mangeot P, Weiss DS, Henry T. AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages. Cell death and differentiation. 2012;19:1709–21. doi: 10.1038/cdd.2012.51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Atianand MK, Duffy EB, Shah A, Kar S, Malik M, Harton JA. Francisella tularensis reveals a disparity between human and mouse NLRP3 inflammasome activation. The Journal of biological chemistry. 2011;286:39033–42. doi: 10.1074/jbc.M111.244079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Wickstrum JR, Bokhari SM, Fischer JL, Pinson DM, Yeh H, Horvat RT, Parmely MJ. Francisella tularensis induces extensive caspase-3 activation and apoptotic cell death in the tissues of infected mice. Infection and immunity. 2009;77:4827–36. doi: 10.1128/IAI.00246-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Meixenberger K, Pache F, Eitel J, Schmeck B, Hippenstiel S, Slevogt H, N’Guessan P, Witzenrath M, Netea MG, Chakraborty T, et al. Listeria monocytogenes-infected human peripheral blood mononuclear cells produce IL-1beta, depending on listeriolysin O and NLRP3. Journal of immunology. 2010;184:922–30. doi: 10.4049/jimmunol.0901346. [DOI] [PubMed] [Google Scholar]
  • 34.Warren SE, Mao DP, Rodriguez AE, Miao EA, Aderem A. Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. Journal of immunology. 2008;180:7558–64. doi: 10.4049/jimmunol.180.11.7558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Kim S, Bauernfeind F, Ablasser A, Hartmann G, Fitzgerald KA, Latz E, Hornung V. Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome. European journal of immunology. 2010;40:1545–51. doi: 10.1002/eji.201040425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Wu J, Fernandes-Alnemri T, Alnemri ES. Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes. Journal of clinical immunology. 2010;30:693–702. doi: 10.1007/s10875-010-9425-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Tsuchiya K, Hara H, Kawamura I, Nomura T, Yamamoto T, Daim S, Dewamitta SR, Shen Y, Fang R, Mitsuyama M. Involvement of absent in melanoma 2 in inflammasome activation in macrophages infected with Listeria monocytogenes. Journal of immunology. 2010;185:1186–95. doi: 10.4049/jimmunol.1001058. [DOI] [PubMed] [Google Scholar]
  • 38.Ozören N, Masumoto J, Franchi L, Kanneganti T, Body-Malapel M, Ertürk I, Jagirdar R, Zhu L, Inohara N, Bertin J, et al. Distinct roles of TLR2 and the adaptor ASC in IL-1beta/IL-18 secretion in response to Listeria monocytogenes. Journal of immunology. 2006;176:4337–42. doi: 10.4049/jimmunol.176.7.4337. [DOI] [PubMed] [Google Scholar]
  • 39.Sauer J, Witte CE, Zemansky J, Hanson B, Lauer P, Portnoy DA. Listeria monocytogenes triggers AIM2-mediated pyroptosis upon infrequent bacteriolysis in the macrophage cytosol. Cell host & microbe. 2010;7:412–9. doi: 10.1016/j.chom.2010.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Sauer J, Pereyre S, Archer KA, Burke TP, Hanson B, Lauer P, Portnoy DA. Listeria monocytogenes engineered to activate the Nlrc4 inflammasome are severely attenuated and are poor inducers of protective immunity. Proceedings of the National Academy of Sciences of the United States of America. 2011;108:12419–24. doi: 10.1073/pnas.1019041108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Tsuji NM, Tsutsui H, Seki E, Kuida K, Okamura H, Nakanishi K, Flavell RA. Roles of caspase-1 in Listeria infection in mice. International immunology. 2004;16:335–43. doi: 10.1093/intimm/dxh041. [DOI] [PubMed] [Google Scholar]
  • 42.Warren SE, Duong H, Mao DP, Armstrong A, Rajan J, Miao EA, Aderem A. Generation of a Listeria vaccine strain by enhanced caspase-1 activation. European journal of immunology. 2011;41:1934–40. doi: 10.1002/eji.201041214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Mueller NJ, Wilkinson RA, Fishman JA. Listeria monocytogenes infection in caspase-11-deficient mice. Infection and immunity. 2002;70:2657–64. doi: 10.1128/IAI.70.5.2657-2664.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Radulovic S, Price PW, Beier MS, Gaywee J, Macaluso JA, Azad A. Rickettsia-macrophage interactions: host cell responses to Rickettsia akari and Rickettsia typhi. Infection and immunity. 2002;70:2576–82. doi: 10.1128/IAI.70.5.2576-2582.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Turco J, Winkler HH. Effect of mouse lymphokines and cloned mouse interferon-gamma on the interaction of Rickettsia prowazekii with mouse macrophage-like RAW264. 7 cells. Infection and immunity. 1984;45:303–8. doi: 10.1128/iai.45.2.303-308.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Smith J, Manoranjan J, Pan M, Bohsali A, Xu J, Liu J, McDonald KL, Szyk A, LaRonde-LeBlanc N, Gao L. Evidence for pore formation in host cell membranes by ESX-1-secreted ESAT-6 and its role in Mycobacterium marinum escape from the vacuole. Infection and immunity. 2008;76:5478–87. doi: 10.1128/IAI.00614-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Welin A, Lerm M. Inside or outside the phagosome? The controversy of the intracellular localization of Mycobacterium tuberculosis. Tuberculosis. 2012;92:113–20. doi: 10.1016/j.tube.2011.09.009. [DOI] [PubMed] [Google Scholar]
  • 48.Wong K, Jacobs WR., Jr Critical role for NLRP3 in necrotic death triggered by Mycobacterium tuberculosis. Cellular microbiology. 2011;13:1371–84. doi: 10.1111/j.1462-5822.2011.01625.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Mishra BB, Moura-Alves P, Sonawane A, Hacohen N, Griffiths G, Moita LF, Anes E. Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome. Cellular microbiology. 2010;12:1046–63. doi: 10.1111/j.1462-5822.2010.01450.x. [DOI] [PubMed] [Google Scholar]
  • 50.Mishra BB, Rathinam VA, Martens GW, Martinot AJ, Kornfeld H, Fitzgerald KA, Sassetti CM. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1β. Nature immunology. 2013;14:52–60. doi: 10.1038/ni.2474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Koo IC, Wang C, Raghavan S, Morisaki JH, Cox JS, Brown EJ. ESX-1-dependent cytolysis in lysosome secretion and inflammasome activation during mycobacterial infection. Cellular microbiology. 2008;10:1866–78. doi: 10.1111/j.1462-5822.2008.01177.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Kurenuma T, Kawamura I, Hara H, Uchiyama R, Daim S, Dewamitta SR, Sakai S, Tsuchiya K, Nomura T, Mitsuyama M. The RD1 locus in the Mycobacterium tuberculosis genome contributes to activation of caspase-1 via induction of potassium ion efflux in infected macrophages. Infection and immunity. 2009;77:3992–4001. doi: 10.1128/IAI.00015-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Welin A, Eklund D, Stendahl O, Lerm M. Human macrophages infected with a high burden of ESAT-6-expressing M. tuberculosis undergo caspase-1- and cathepsin B-independent necrosis. PloS one. 2011;6:e20302. doi: 10.1371/journal.pone.0020302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Abdallah MA, Bestebroer J, Savage ND, de Punder K, van Zon M, Wilson L, Korbee CJ, van der Sar AM, Ottenhoff TH, van der Wel NN, et al. Mycobacterial secretion systems ESX-1 and ESX-5 play distinct roles in host cell death and inflammasome activation. Journal of immunology. 2011;187:4744–53. doi: 10.4049/jimmunol.1101457. [DOI] [PubMed] [Google Scholar]
  • 55.Manzanillo PS, Shiloh MU, Portnoy DA, Cox JS. Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages. Cell host & microbe. 2012;11:469–80. doi: 10.1016/j.chom.2012.03.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Saiga H, Kitada S, Shimada Y, Kamiyama N, Okuyama M, Makino M, Yamamoto M, Takeda K. Critical role of AIM2 in Mycobacterium tuberculosis infection. International immunology. 2012;24:637–44. doi: 10.1093/intimm/dxs062. [DOI] [PubMed] [Google Scholar]
  • 57.Yang Y, Zhou X, Kouadir M, Shi F, Ding T, Liu C, Liu J, Wang M, Yang L, Yin X, et al. The AIM2 inflammasome is involved in macrophage activation during infection with virulent Mycobacterium bovis strain. The Journal of infectious diseases. 2013 doi: 10.1093/infdis/jit347. [DOI] [PubMed] [Google Scholar]
  • 58.Shah S, Bohsali A, Ahlbrand SE, Srinivasan L, Rathinam VA, Vogel SN, Fitzgerald KA, Sutterwala FS, Briken V. Cutting Edge: Mycobacterium tuberculosis but Not Nonvirulent Mycobacteria Inhibits IFN-β and AIM2 Inflammasome-Dependent IL-1β Production via Its ESX-1 Secretion System. Journal of immunology. 2013 doi: 10.4049/jimmunol.1301331. [DOI] [PMC free article] [PubMed] [Google Scholar]

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