Cellular and molecular interactions underlying the peripheral immune responses to blood-stage malaria infections

Kieran Tebben; Rosita Asawa; David Serre; Kirsten E Lyke

doi:10.1093/immhor/vlag016

. 2026 Apr 23;10(4):vlag016. doi: 10.1093/immhor/vlag016

Cellular and molecular interactions underlying the peripheral immune responses to blood-stage malaria infections

Kieran Tebben ^1,^2,^✉, Rosita Asawa ^3,⁴, David Serre ⁵, Kirsten E Lyke ⁶

PMCID: PMC13102483 PMID: 42019947

Abstract

Malaria, caused by Plasmodium species, is one of the most widespread illnesses globally, affecting millions of individuals each year. The complex life cycle of these parasites requires a multifaceted approach from the human immune system to respond to infection. Additionally, Plasmodium parasites have coevolved in primates and developed numerous immune evasion mechanisms to escape human immune defenses. Here, we provide an up-to-date review of the human immune responses to blood-stage malaria, as well as the parasite immune evasion mechanisms during this part of the life cycle.

Keywords: host-pathogen interactions, immunology, malaria

Malaria

Malaria is a vector-borne disease caused by infection with 1 of 5 species of protozoan Plasmodium parasites following the bite of an infected female Anopheles mosquito.¹ Approximately 3 billion people, almost half of the world’s population, are at risk for malaria,² making this disease one of the leading public health issues worldwide. In 2023, there were 263 million global cases of malaria, with the most severe cases and the highest burden of disease occurring in sub-Saharan Africa and caused by Plasmodium falciparum.²

Malaria is characterized by cyclical fevers,³ that recur every 24 to 36 h depending on the parasite species,¹ and flu-like symptoms caused by the asexual replication of the parasites within red blood cells. P. falciparum, the dominant species in sub-Saharan Africa, can also lead to severe symptoms, particularly in children under 5 yr of age,¹^,⁴ which can be classified into 3 main syndromes: severe malarial anemia, cerebral malaria, and acute respiratory distress.⁵ If not treated rapidly, severe malaria is often deadly⁴^,⁵ and is a leading cause of mortality in children under 5 yr of age in sub-Saharan Africa.⁵

All human-infecting Plasmodium species share the same life cycle, including development in a mosquito vector and human host.⁶ Within the mosquito, Plasmodium parasites develop from male and female gametes in the midgut to transmissible salivary gland sporozoites within 2 wk.¹ When an infective mosquito takes a blood meal, sporozoites are injected into the skin of the mammalian host and rapidly travel through the blood stream to the liver.¹ After infection of a hepatocyte, sporozoites develop into liver schizonts, which eventually rupture and release merozoites in the circulation.¹ Merozoites infect red blood cells (RBCs) and begin the intraerythrocytic development cycle (IDC), first developing into ring stage parasites (rings).¹ Within the infected red blood cells (iRBCs), the IDC continues as rings develop into trophozoites and then blood schizonts.¹ Schizonts eventually rupture and release merozoites into the circulation to infect new RBCs and begin a new IDC.¹ This IDC leads to an increase in parasitemia up to 32× each cycle or every 24 to 72 h (depending on the Plasmodium species).⁷ A subset of blood-stage parasites become sexually committed and develop into male or female gametocytes⁸ that, when ingested during a blood meal, lead to transmission to the mosquito.

Immunopathology induced by the asexual blood-stage parasites is responsible for all symptoms of malaria.¹^,⁵^,⁹ The immunopathology of symptomatic malaria is complex and multifactorial but involves endotoxins released into the circulation when schizonts rupture iRBCs and TNFα secreted by macrophages upon ingestions of merozoites and iRBCs.⁵ Symptoms of malaria typically arise when inflammation reaches a critical, although undefined, threshold and the patient feels ill.⁵

Immune responses to the P. falciparum IDC

The complex life cycle of Plasmodium parasites within the human host leads to unique immune responses to each developmental stage.¹⁰^,¹¹ In this review, we focus on the asexual blood stages (i.e. the IDC) of P. falciparum that induce robust, systemic inflammation and are responsible for all malaria symptoms.¹^,¹⁰ The immune response to the liver stages, which were long considered asymptomatic, were recently reviewed by Abuga et al.¹² Blood-stage parasites interact with a variety of immune cells from the innate and adaptive immune systems, described in more detail subsequently. Some immune memory also develops to these stages over time and repeated exposures, leading to a reduction in symptom severity in older patients, but rarely providing sterile immunity.¹⁰^,^13–15 Here, we briefly review the major cell types of the innate (Fig. 1A) and adaptive (Fig. 1B) immune system that are responsible for the anti-Plasmodium immune response, as well as mechanisms by which P. falciparum evades this immune detection (Fig. 2).

For image description, please refer to the figure legend and surrounding text. — Innate and adaptive immune response to blood-stage *P. falciparum*. (A) Innate immune response: iRBCs are recognized by neutrophils through binding of intercellular adhesion molecule 1 (ICAM1) to PfEMP1s expressed on the surface of iRBCs leading to release of reactive oxygen species (ROS)/nitric oxides (NOs). Activated neutrophils degranulate to release NETs to kill extracellular merozoites. Circulating antibodies bind to merozoites and recruit C1 to activated the complement pathway. Extracellular merozoites are phagocytosed by antigen-presenting cells (APCs) via FCγRIII binding leading to release of pathogen-associated molecular patterns (PAMPs) in the endosome. TLR7, TLR8, and TLR9 recognize PAMPs to stimulate a type I IFN response and release of IL-18. AIM2 in the cytosol, enhanced by hemozoin, recognizes double-stranded DNA and leads to the generation of IL-1β, which activates NK cells to release IFNγ. (B) Adaptive immune response: APCs activate naïve CD4+ T cells through MHC class II (MHC-II)–TCR interactions stabilized by CD4. The secondary release of IL-12 from APCs polarizes CD4+ T cells toward a Th1 phenotype, which release IFNγ to directly reduce parasitemia. CD8+ T cells are activated through MHC-I–TCR binding, stabilized by CD8, to release perforin and granzyme, which directly target extracellular merozoites. In the spleen, Tfh cells stimulate naïve B cells through MHC-II–TCR interactions resulting in differentiation to antibody-producing plasma cells.

Innate immune responses

Complement

The complement system is an ancient component of the innate immune system, predating jawed vertebrates,¹⁶ and one of the first arms of the immune response to encounter parasites in the blood.¹⁷ Merozoites, the only extracellular stage within the IDC, can fix complement directly on the cell surface and are susceptible to complement-mediated lysis and killing, particularly after complement fixation via the classical pathway, with circulating antibodies interacting with merozoite surface antigens such as merozoite surface proteins (MSPs),¹⁸ PfRH5, and AMA1.¹⁹^,²⁰ Complement fixation on the merozoite surface can also enhance phagocytosis by phagocytes and antigen-presenting cells²¹ and recruitment of additional innate immune cells.¹⁷ In the absence of other complement components, fixation of C1q/antibody complexes to the merozoite surface can also efficiently prevent merozoite invasion of RBCs.¹⁹

The more mature, intracellular, stages of the P. falciparum IDC remodel the surface of the iRBC with parasite proteins that can be recognized by circulating antibodies²² but overall are less susceptible to complement-mediated killing. Despite the presence of antigenic targets, prior work has demonstrated relative protection of iRBCs from complement activation, and particularly complement-mediated lysis.²³ One of the most well-characterized and prevalent targets of anti-P. falciparum antibodies on the iRBC surface is P. falciparum erythrocyte membrane protein 1 (PfEMP1), but extreme sequence variation in PfEMP1 between different parasites challenges the development of specific antibodies.²⁴ Additionally, despite evidence of opsonization,²⁵ the structure of PfEMP1s on the RBC surface²⁵ and binding by IgM²⁶^,²⁷ seems to preclude complement activation on iRBCs.

Innate immune sensing of P. falciparum

Innate immune sensing of Plasmodium parasites, including P. falciparum, has been extensively reviewed elsewhere.²⁸ Briefly, some of the most well-characterized P. falciparum molecules recognized by the host cells (pathogen-associated molecular patterns) are glycosylphosphatidylinositols.²⁹^,³⁰ Plasmodium glycosylphosphatidylinositols are recognized by Toll-like receptor 2 (TLR2)³⁰ and lead to the production of proinflammatory cytokines.²⁹ Upon parasite digestion by phagocytes, P. falciparum DNA is sensed by TLR7 and TLR9³¹ on the inner membrane of endolysosomes or by the cytosolic DNA sensor, AIM2.³² Signaling through TLR7 and TLR9 initiates a type I IFN response, leading to the release of proinflammatory cytokines IFNα and IFNβ.³³ Sensing through AIM2 is enhanced by hemozoin, a crystalline byproduct of hemoglobin digestion by the parasites, which can itself be sensed by the NLRP3 inflammasome,³² both of which lead to cleavage and release of IL-1β.³⁴ Similarly, parasite RNA can be sensed by TLR8 on the inner membranes of monocyte phagolysosomes³⁵^,³⁶ and leads to the release of IL-1β and IL-18, leading to the downstream release of IFNγ by natural killer (NK) cells.³⁵ Together, this proinflammatory cytokine environment contributes to triggering fever and the flu-like symptoms of malaria.

Neutrophils

Neutrophils, the most abundant white blood cell, rapidly respond to blood-stage Plasmodium parasites.^37–39 Neutrophils can kill free merozoites or iRBCs via phagocytosis, or by releasing toxic molecules such as reactive oxygen species or neutrophil extracellular traps (NETs).³⁹ Neutrophils can interact directly with iRBCs via intercellular adhesion molecule 1 on the neutrophil surface binding to CD36-binding PfEMP1s, leading to phagocytosis and killing of the iRBC.⁴⁰ Phagocytosis of merozoites or iRBCs can be enhanced by complement-mediated opsonization or antibody binding to parasite antigens on the iRBC surface that interact with complement and Fcγ receptors on neutrophils³⁷^,⁴¹ or by release of proinflammatory cytokines.⁴² Phagocytosis then triggers killing of the parasites or iRBCs by reactive oxygen species⁴² or microbicidal granule proteins⁴³ within the neutrophil. Like phagocytosis, parasite-specific antibodies can also enhance reactive oxygen species release and neutrophil-mediated parasite killing (i.e. antibody-dependent respiratory burst).⁴⁴

In addition to phagocytosis, neutrophils can immobilize and kill parasites through degranulation of their genetic material and antimicrobial granules as NETs.⁴⁵^,⁴⁶ Parasite molecules such as uric acid (a byproduct of purine salvage),⁴⁷ as well as proinflammatory cytokines,⁴⁸ can increase NET production. NETs have been reported to be important for not only control of parasitemia,⁴⁹ but also exacerbation of immunopathology.⁵⁰ While neutrophils are essential for initial control of parasitemia and for reducing the pathogen load, their activation has been linked to immunopathology³⁸^,³⁹^,⁵¹ and severe malaria,³⁷^,⁵² potentially via inflammation-induced endothelial damage in the tissues, although the precise mechanisms remain unclear.

Monocytes and macrophages

In the circulation, monocytes are also major contributors of phagocytosis and killing of iRBCs, with 2 subsets of cells, intermediate/inflammatory (CD14+CD16+) and nonclassical (CD16+) monocytes, being particularly efficient.^53–55 Nonopsonic phagocytosis is mediated by monocyte TLR2 and TLR4 stimulation and interactions of the monocyte surface protein CD36 with PfEMP1s on the iRBC surface.⁵⁶ Opsonic phagocytosis requires opsonization of merozoites or iRBCs with antibodies and complement proteins, which interact with FcγRIII on the monocyte surface, triggering phagocytosis.⁵⁷ While both mechanisms of phagocytosis can lead to parasite killing, only opsonic phagocytosis leads to downstream monocyte activation and release of proinflammatory cytokines such as TNF and IL-1β.⁵⁵^,⁵⁸

Because macrophages primarily exist within tissues, it is difficult to characterize their interactions with blood-stage parasites in humans and many studies so far have relied on mouse models to speculate about their function during human infections.⁵⁵ Within tissues, macrophages typically interact with sequestered iRBCs (containing mature asexual stage parasites). Similarly to monocytes, macrophages can perform nonopsonic phagocytosis via CD36⁵⁹ or opsonic phagocytosis via antibodies and complement.⁶⁰ Again, only opsonic phagocytosis is associated with macrophage activation and proinflammatory cytokine production.⁶⁰

Similarly to neutrophils, proinflammatory cytokine release by monocytes and macrophages can contribute to both control of parasite load via further activation of the phagocytes,⁶¹^,⁶² as well as immunopathology⁵⁵ and severe malaria syndromes.⁵²^,⁶³

Dendritic cells

Dendritic cells (DCs) are an important bridge between the innate response and both branches of the adaptive immune system in response to blood-stage malaria.⁶⁴ Generally, DCs phagocytose P. falciparum merozoites or iRBCs similarly to monocytes and macrophages. After phagocytosis, DCs become activated, increasing expression of the major histocompatibility complex (MHC) class 1 or 2 and costimulatory molecules on their surface.⁶⁴ After activation, DCs travel to the spleen or secondary lymphoid tissues⁶⁴ to initiate T cell responses via antigen presentation, costimulation, and release of proinflammatory cytokines, which initiates the adaptive immune response and/or recruits and activates additional innate immune cells to the site of infection.⁶⁴ There are still little data from human infection, but in mouse models, different subsets DCs have been shown to induce both parasite-specific CD4 and CD8 T cell responses⁶⁵^,⁶⁶ after interaction in the blood with parasites or iRBCs. While peripheral CD4 T cell responses can lead to control of parasitemia and disease, initiation of a peripheral CD8 T cell response has been associated with cerebral malaria pathogenesis.⁶⁵

DC responses to P. falciparum vary with transmission intensity and their efficacy in generating an effective immune response for clearance of the parasites is directly impacted by the parasites themselves. In high-transmission settings, a particular subset of highly MHC class II–expressing DCs (by flow cytometry identification of HLA-DR), BDCA-3⁺ cDC1s,^67–69 was found to be expanded after infection, while other DC subtypes, showed generally reduced expression of MHC class II,⁶⁸^,⁷⁰ detected by flow cytometry, and a reduced ability to stimulate T cells.⁶⁷ The functional consequences of this observation remain unclear but warrant further investigation with human cohorts. In low-transmission settings, DCs isolated from peripheral blood of P. falciparum–infected patients were noted to be apoptotic and unable to be activated or to stimulate T cell responses.⁷¹ Controlled human malaria infection studies have also observed a decrease in expression of MHC class II on certain DC subsets, along with reduced IL-12 production,⁷² suggesting reduced ability to productively bridge the innate and adaptive immune systems. Additional work has suggested a critical threshold of parasite biomass to induce this DC dysregulation.⁷³ Crosstalk between different DC subsets may also be key to their response to P. falciparum,⁷⁴^,⁷⁵ but further work is necessary to fully disentangle the relationship between protective immune responses generated by DCs during infection and their dysregulation.

NK cells

NK cells have 3 major pathways of activation: cytokine activation via IL-12 and IL-18, antibody-dependent cell-mediated cytotoxicity (ADCC), and the loss of inhibitory signal by damaged or diseased cells. In malaria infections, a positive association between IFN-γ production and protection from malaria^76–78 brought attention to the interplay between NK cells and P. falciparum infection. NK cells can directly reduce parasitemia by targeting and destroying iRBCs through antibody-dependent and antibody-independent mechanisms. In the presence of IgG specific for P. falciparum antigens on the iRBC surface, NK cells can adhere to iRBCs via leukocyte integrin αLβ2 before releasing perforin and granzyme to selectively lyse iRBCs, exposing the parasitophorous vacuole for phagocytosis by monocytes.⁷⁹

These cells can also, indirectly, lead to destruction of iRBCs through the release of IFNγ,⁸⁰ which activates macrophages and leads to increased phagocytosis of iRBCs.³⁵ Additionally, expression of PD-1 on NK cells in malaria-exposed individuals is associated with diminished NK cytotoxicity but improved ADCC, indicating that PD-1 may contribute to the skewing of NK cells toward ADCC activity seen during malaria infection.⁸¹

Recent work has highlighted a phenotypically and transcriptionally unique population of NK cells that do not express CD56, a classical NK cell marker, that appear to be important to parasitemia control.⁸²^,⁸³ These cells were found to expand rapidly upon repeated malaria exposure, and their expansion was associated with protection against high parasite density and symptomatic malaria.⁸³ Interestingly, maintenance of this population appears to be exposure dependent and rapidly declines without Plasmodium exposure.⁸³ Further work found that activation of these unique NK cells is influenced by both host and parasite factors, again highlighting the complexity of the interplay between P. falciparum and the human immune system.⁸² NK cells isolated from malaria-exposed Ugandan donors displayed enhanced ADCC and in vitro studies measured enhanced NK cell degranulation in response to P. falciparum schizonts when cultured with plasma from donors in high-transmission areas.⁸² This reinforces the impact of P. falciparum exposure on influencing the NK cell response⁸² and highlights the need for further research to fully characterize both how NK cells contribute to the anti-Plasmodium response and how parasite exposure influences this response to better understand how to exploit these interactions for treatment or prevention of malaria.

While traditionally classified as innate immune cells, NK cells have also been shown to demonstrate a “memory” or “memory-like” immunological response leading to increased cytokine production and cytotoxic effects upon restimulation.⁸⁴ This memory-like phenotype, as well as their potential exposure-dependent activation, is similar to how the adaptive immune system interacts with P. falciparum.

P. falciparum blood-stage evasion of the innate immune response

Immune evasion mechanisms in Plasmodium spp. have been extensively reviewed elsewhere,¹¹^,⁸⁵^,⁸⁶ but here we highlight the main mechanisms of evasion of the innate immune system in humans. In order to survive in circulation, parasites must avoid the early innate phase of the immune response such as complement activation and, ultimately, opsonization and phagocytosis. During the IDC, the RBC, which does not express MHC molecules, serves as an immunological sanctuary. This is a key mechanism of immune evasion, however the merozoites, the only extracellular blood stage, remain susceptible to immune attack.⁸⁷ Merozoites recruit complement inhibitory factors, C1-INH and factor H,⁸⁸ to their surface to avoid complement fixation and activation. They also avoid detection by circulating antibodies, which can block invasion and/or lead to complement activation, through sequence variation of antigens on their surface and through functional redundancy of proteins to preserve invasion machinery if one molecule is blocked.⁸⁷

During the intraerythrocytic stages of the IDC, P. falciparum iRBCs also recruit complement inhibitory factors, factor H,⁸⁹ and plasminogen⁹⁰ to avoid complement fixation. Antibodies against PfEMP1, the major surface antigen of P. falciparum iRBCs, seem to be unable to fix and activate complement,²⁵ potentially due to the structure of knobs on which PfEMP1 is presented.²⁵ Infected RBCs also form rosettes, or clusters of uninfected RBCs surrounding iRBCs, via binding of iRBCs to complement receptor 1 on the uninfected RBC surface,⁹¹ which physically hide parasite surface antigens from circulating antibodies or immune cells (Fig. 2A).⁹² While avoiding complement activation, iRBCs must also avoid phagocytosis by circulating phagocytes or resident phagocytes in the spleen. By avoiding complement activation, parasites reduce opsonization, which prevents their efficient phagocytosis in circulation. P. falciparum parasites, uniquely, sequester in the tissues later in the IDC via interactions of PfEMP1 with endothelial surface markers on the tissue microvasculature,⁹²^,⁹³ which limits their interaction with phagocytes to tissue-resident cells. Tissue sequestration also prevents iRBCs from being filtered through the large population of resident phagocytes in the spleen.⁹²

In addition to simply avoiding immune activation, Plasmodium parasites also actively dampen the innate immune response. P. falciparum iRBCs express high levels of CD47 on their surface, which interacts with inhibitory receptors on the macrophage surface (e.g. SIRPα) and decreases phagocytosis.⁹⁴ Additionally, during infection, complement receptor 1 expression is reduced on monocytes and macrophages by an unknown mechanism, reducing complement-mediated phagocytosis.⁹¹ Monocyte phagocytosis of iRBCs is inhibited by the production of insulin growth factor binding protein 7.⁹⁵ Even after successful phagocytosis, phagocytes and neutrophils have a limited capacity to digest and remove iRBCs, due to hemozoin toxicity, before becoming overloaded with this pigment and unable to perform their function in clearing parasites.⁹⁶^,⁹⁷

Dysregulation of the DC response is a critical mechanism of P. falciparum immune evasion, as the initiation of the adaptive immune response critically depends on an appropriate initial DC response to the parasites (Fig. 2B). P. falciparum’s ability to dysregulate DCs is not yet completely understood, but several mechanisms have been proposed. Hemozoin exposure from iRBCs can partially impair DC maturation.⁹⁸ Direct interaction of iRBCs and DCs also seems to impair DC maturation, antigen processing, and T cell stimulation,⁹⁹^,¹⁰⁰ but the mechanism underlying this impairment is still unknown. The mechanisms by which P. falciparum induce DC apoptosis in vivo, described previously, are not yet understood but will be key to understanding protective antimalarial immunity and the improvement of existing vaccines.

Adaptive immune responses to blood-stage Plasmodium parasites

CD4+ T helper cells

Peripherally circulating CD4+ T helper (Th) cells play a central role in responding to blood-stage P. falciparum (while liver-resident CD8+ T cells are critical for the pre-erythrocytic immune responses in the liver).¹⁰¹ Innate immune cell detection of different parasite antigens by different receptors (reviewed previously) leads to particular cytokine production according to the specific antigen and receptor bound?. Cytokines released from antigen-presenting cells polarize CD4+ Th cells toward various phenotypes, which could be skewed by the cell type and mechanism by which these cells are being activated. These phenotypes have been reviewed in greater detail elsewhere¹⁰²^,¹⁰³; we briefly review the major phenotypes subsequently. P. falciparum–specific antigen-presenting DCs release cytokines such as IL-12 and IL-6 (predominantly via TLR2 and TLR8 sensing of iRBCs),¹⁰⁴ polarizing Th cells toward a Th1 phenotype.¹⁰³ Th1 polarized cells play a large role in T cell–mediated control of blood-stage P. falciparum, primarily through release of IFNγ^74,.105,106 While the exact mechanism by which IFNγ release contributes to parasitemia control is not yet clear,¹⁰³ data from mouse models suggest that this cytokine activates macrophages, increasing their ability to phagocytose iRBCs.^107–109 A subset of these cells also produce macrophage colony-stimulating factor, further promoting the activity of macrophages in controlling parasitemia.¹¹⁰ While IFNγ seems to be critical in reducing parasite burden, it can also contribute to pathogenesis by impairing parasite-specific B cell responses.¹⁰³ A unique subset of Th1 cells produce both proinflammatory IFNγ and anti-inflammatory IL-10 in response to stimulation from IL-27¹¹¹ and type I IFNs.¹¹² While their precise role in the antimalarial immune response remains elusive, a higher abundance of these cells has been associated with increased risk of malaria in pregnancy,¹¹³ and IL-10 production from these cells has been associated with both reduced immunopathology¹¹⁴^,¹¹⁵ and impaired ability to control parasitemia.¹¹⁶

While Th1 is the dominant phenotype in response to P. falciparum blood stage, the role of other Th phenotypes is not completely understood. Th2 polarized cells release IL-4, which can support B cell class switching,¹¹⁷^,¹¹⁸ but their role in P. falciparum blood-stage infection is yet to be confirmed. Th17 polarized cells capable of production of IL-17, which recruits neutrophils,¹¹⁹ have been identified in 1 Malian cohort with P. falciparum,¹²⁰ but their role in the antimalarial immune response is still unclear.

T follicular helper cells

T follicular helper cells (Tfh) bridge the cellular and humoral arms of the adaptive immune system and can be identified by expression of BCL-6, CXCR5, and PD1.¹²¹ After their own activation and development, promoted by IL-6 and IL-21, Tfh cells interact with B cells via production of IL-21¹²² and expression of ICOS¹²³^,¹²⁴ to stimulate B cell maturation and survival within the germinal center of the secondary lymphoid tissues.¹²⁵ During malaria, Tfh cells have been identified as critical in promoting the B cell–mediated generation of P. falciparum antigen-specific antibodies, which are important for controlling parasitemia,¹²⁶^,¹²⁷ and for the differentiation of naïve B cells into memory B cells (MBCs) and long-lived plasma cells,¹⁰³^,¹²⁷ which are critical for long-lasting immunity to the parasites.

In addition to supporting B cell responses, Plasmodium-specific Tfh cells can adopt partial phenotypes from other T cell subsets.¹²⁸ Tfh cells with a Th1-like phenotype (Tfh-Th1) secrete IFNγ,¹²⁸ a cytokine linked to parasitemia reduction and promotion of protection upon reinfection,¹²⁹ but, surprisingly, Tfh-Th1cells have been shown to provide compromised or “atypical” B cell help during infection.¹²⁸ Both IFNγ¹¹²^,¹²⁴^,¹³⁰ and type I IFNs¹²⁴ have somewhat paradoxically been linked to impaired Tfh function in mouse models. Controlled human malaria blood-stage infections have demonstrated increased expression of CXCR3 on Tfh-Th1 cells and an association with ineffective antibody formation and reduced malaria immunogenicity.¹³¹ Tfh cells with a regulatory T cell phenotype can produce IL-10 in the germinal center.¹³² Interestingly, recent work has shown that extrafollicular IL-10 is critical for the Tfh development and maturation,¹³³ but the role of this cytokine within the germinal center during malaria is still unclear and could contribute to the poor memory response generated by these parasites.

Most of our current knowledge of germinal center Tfh cells comes from mice due to sampling accessibility. However, human studies have demonstrated activation of Tfh cells toward a Th1 phenotype in the circulation after P. falciparum exposure,¹²⁸ and activation of this subset increases with age.¹³⁴ These cells seem to be poorly able to activate naïve B cells and produce IFNγ,¹²⁸ which has been linked to development of atypical, exhausted MBCs¹³⁵ and short-lived plasma cells.¹³⁶ Some studies have linked circulating Tfh cells with a Th2 phenotype to functional antibody production,¹²⁷^,¹³¹ but further work is needed to understand how this phenotype is induced. Interestingly, only Th17-Tfh cells have been associated with subsequent protection from malaria¹³⁴ in humans, although their precise function during malaria is not yet characterized.

Regulatory T cells

Regulatory T cells (Tregs) act to regulate the inflammation induced by other cell types in response to infections by releasing anti-inflammatory cytokines such as IL-10, and limit immunopathology that can be caused by chronic inflammation.¹³⁷ Their role in malaria is still controversial and seems to antagonize the productive immune control of the parasites.¹³⁸ In humans, the Treg population expands during the P. falciparum blood stage, and larger numbers of Tregs are associated with worse clinical outcomes.¹³⁹ Some speculate that expansion of Tregs during severe infection is a consequence of the increased parasitic load, which results in paradoxical immune suppression and worse infection control.¹⁰³ Some research suggests a beneficial role for Tregs_, mitigating some of the sequelae of malaria. People of Peuhl ethnicity in West Africa have been shown to have a genetic enhancement in Treg production, correlating with enhanced protection against malaria compared with other ethnicities.¹⁴⁰^,¹⁴¹ Recent work has also shown that dihydroartemisinin, a common antimalarial drug, can also induce the expansion of these cells.¹⁴² Future work is important to understand how and why this population expands during malaria and their functional consequences, particularly as it might relate to age of the infected individual.

After expansion, Tregs secrete IL-10, which leads to decreased production of proinflammatory cytokines from other cell types¹³⁹ and can limit symptoms caused by systemic inflammation, but also allows parasite growth to continue. The precise mechanisms of Treg function during malaria are still incompletely characterized, but the expression of CTLA4 seems to impair germinal center reactions,¹⁴³ and further work is needed to fully understand the role of these cells in malaria.

γδ T cells

γδ T cells are a specialized subset of unconventional T cells that perform both innate-like and adaptive-like functions, including the production of proinflammatory cytokines, MHC-independent antigen presentation, cytotoxic killing, and promotion of DC and B cell maturation.¹⁴⁴^,¹⁴⁵ Their role in malaria immunity is a rapidly expanding field of research and much remains unknown, but we have briefly summarized some main findings here. These T cell receptor (TCR)–containing cells were originally considered to be innate-like with no ability to form long-term responses, but long-term elevation in the proportion of peripheral γδ T cells has been found in Plasmodium-exposed humans following both irradiated sporozoite vaccination¹⁴⁶ or controlled experimental infection of human volunteers.¹⁴⁷ These cells are characterized by the specific γ and δ TCR chains they express and particular subsets rapidly proliferate following a primary P. falciparum infection to produce a robust proinflammatory cytokine response¹⁴⁸^,¹⁴⁹ and granulysin-containing cytotoxic granules,¹⁵⁰^,¹⁵¹ associated with protection from clinical malaria.¹⁵²^,¹⁵³ However, the exact mechanism behind γδ T cell expansion, including which subsets expand and which do not, and how this leads to protection from malaria is still poorly understood. Initial exposure is characterized by a dominant innate-like vδ2 T cells. Repeated exposure to Plasmodium parasite leads to expansion of vδ1 T cells, characterized by waves of clonal selection in the vδ1 TCR repertoire and differentiation into an adaptive vδ1effector morphologies. These cells can both recognize parasite phosphoantigens and trigger an adaptive response, and also directly lead to parasite killing via phagocytosis of iRBCs and production of cytotoxic granules. However, diminishing expansion of these cells and loss of functional activity over time has also been observed, representing a potential immunological tolerance mechanism contributing to clinical manifestations of malaria.¹⁵²^,¹⁵⁴ Further work is currently being done and is much needed to fully understand how these cells contribute to immune response to malaria and how the parasites interact with them in the peripheral blood.

B cells

B cells are responsible for the humoral response to Plasmodium, which primarily involves the generation and secretion of Plasmodium antigen-specific antibodies.¹⁵⁵ Naïve B cells interact with Plasmodium antigens in the peripheral blood or the immune follicles via the B cell receptor and become activated.¹⁵⁵ After activation, B cells travel to the secondary lymphoid tissues where they undergo clonal expansion and further mature.¹⁵⁶ In the secondary lymphoid tissues, DCs and Tfh cells support B cell maturation toward two lineages, plasmablasts or germinal center B cells (GCBs),¹⁴ by providing important cytokines (such as IL-21, IL-6, and BAFF) and costimulatory molecules (such as CD40L and ICOS).¹⁵⁵

B cells that mature into plasmablasts rapidly produce and secrete antibodies within days of encountering a pathogen but primarily produce low-affinity IgM type antibodies.¹⁴ These antibodies can help to control pathogens while more specific B cell responses develop over weeks to months but are short-lived and are not found in the blood after the infection has cleared.¹⁴ In mouse models of malaria, plasmablasts expand during infection but seem to contradict the development of a productive immune response.¹³⁶ These cells have been shown to act as a nutrient sink, impairing the development of a productive humoral immune response.¹³⁶

GCBs enter a specialized area within the germinal center and can further mature into MBCs or long-lived plasma cells to provide lasting humoral immunity to Plasmodium infection.¹⁴ In the germinal center, GCBs form sustained interactions with Tfh cells to facilitate their development to either cell type,¹⁴ and undergo somatic hypermutation and class-switch recombination to improve the affinity of their secreted antibodies to their antigen.¹⁵⁵ Additionally, GCBs primarily express higher affinity IgGs rather than IgM.¹³⁷ GCBs that differentiate to long-lived plasma cells reside in the bone marrow where they stably secrete anti-Plasmodium antibodies for years after infection.¹⁴ MBCs remain in the peripheral blood or secondary lymphoid tissues for years after infection and can rapidly expand and activate upon secondary encounters with their antigen (discussed more subsequently).¹⁴ Several mechanisms have been proposed to explain the inefficient generation of a humoral immune response to P. falciparum, including poor Tfh help and aberrant dampening of the immune response by Th1 skewed Tfh cells and Tregs,¹⁴ but work is still needed to completely understand these mechanisms and their consequences. Aside from inefficient development in the germinal center, malaria has also been shown to dysregulate the B cell niche in the bone marrow by reducing CXCL12 and IL-7 production,¹⁵⁷ which impairs the survival and subsequent development of B cell progenitors and plasma cells.

Antibodies

Antibodies are known to play a critical role in combating blood-stage P. falciparum infection and controlling the development of clinical symptoms. The peripheral immune response to P. falciparum is driven mainly by the IgG antibody response, in particular by the IgG1 and IgG3 subclasses that have high-affinity Fc receptors.¹⁵⁸ Antimalaria antibodies act in several ways to control infection including the neutralization of Plasmodium ligands,¹⁵⁹ induction of complement,¹⁸ and enhanced phagocytosis of merozoites.¹⁶⁰ Protection from malaria has been strongly associated with high antibody levels to several blood-stage and pre-erythrocytic stage proteins, the most promising of which includes AMA1. Antibody titers specific for AMA1, generated from any cell type, have been associated with clinical protection from malaria symptoms,¹⁶¹^,¹⁶² and anti-AMA1 antibodies have been shown to inhibit invasion of RBCs by merozoites.¹⁶³

Development of adaptive immune memory to blood-stage parasites

Both the cellular and humoral branches of the adaptive immune response have the capacity to develop into pathogen-specific memory T or B cells that remain in circulation after an infection has resolved and can respond and expand rapidly upon secondary exposure, in some cases providing sterile protection from subsequent infection with a pathogen.¹³⁷ Memory responses to malaria were first hypothesized because of the development of clinical protection from disease with repeated exposures to Plasmodium parasites.¹⁵ As children in endemic areas age and experience more parasitic exposures, they can develop naturally acquired immunity,¹⁶⁴ first becoming protected from severe malaria early in childhood, and eventually from most symptomatic disease later in adolescence.¹⁵ Both T and B cell memory development has been measured in both mouse models and human malaria,¹⁶⁴ but the exact mechanisms of each, and how Plasmodium parasites actively evade this development, are still incompletely understood.

T cell–mediated memory

T cell–mediated memory to blood-stage Plasmodium parasites is less well characterized than B cell memory (see the following). Plasmodium blood stage–specific memory CD4+ T cells have been observed but can display a mixed phenotype with characteristics of Th1 cells, Tfh cells, and Tregs, and the protective ability of these polyfunctional cells is not yet known.¹⁰³ Memory T cells with a Th1 phenotype have been observed in mouse models and appear to be protective upon secondary Plasmodium challenge.¹³⁰^,¹⁶⁵ Th1 cells, in general, secrete IFNγ, which has been linked to the development of atypical memory B cells (aMBCs),¹⁰³ potentially linking T cell–mediated immunity to dysfunction in a different immune compartment, although memory Th1 cells have been shown to promote B cell development upon reinfection.¹³⁰ Memory T cells with a Tfh phenotype have also been observed, but their mechanism of protection against malaria is currently unknown.¹⁰³ Access to memory T cells, which can reside within the tissues or secondary lymphoid organs, rather than in the peripheral blood, primarily complicates studies of their function and require multiple tissue samples over time to catch a peripheral response.¹⁶⁶

B cell–mediated memory

Humoral memory responses to Plasmodium have been more extensively characterized as antibodies produced by MBCs have been shown to be essential to the development of naturally acquired immunity over time. The repertoire of parasite-specific antibodies rapidly expands with repeated Plasmodium exposures to cover a broad array of parasite antigens,¹⁶⁷^,¹⁶⁸ improving clinical protection. Although antibodies have been shown to play a large role in clinical immunity to malaria, MBCs seem to have a transmission-dependent development pattern, with inefficient development in high transmission settings.¹⁶⁹ In settings with seasonal transmission, MBC populations develop slowly over time with age and exposure, with disproportionately low frequencies of MBCs observed after each transmission season that wane during the low exposure dry season.¹⁶⁸^,¹⁷⁰ In low-transmission settings, MBCs are generated at expected frequencies and are long-lived.¹⁷¹ While this transmission-dependent development of MBCs is not yet well understood, previous work has suggested that dysregulated Tfh responses and/or inflammatory cytokines might contribute.¹⁶⁹ In both human malaria¹²⁸ and mouse models,¹⁷² circulating Tfh cells express a Th1-associated transcription factor, T-bet, after acute malaria, and this phenotype has been linked to reduced support for MBC generation. IFNγ has also been shown in mouse models to directly impair the germinal center reaction,¹⁷³ which is key to MBC development. Further work is important to determine the mechanisms by which either or both mechanisms lead to impaired MBC generation during malaria.

Atypical MBCs

In addition to decreased production of MBCs, persistent malaria exposure is also associated with development of MBCs with an atypical phenotype and function, termed aMBCs, although their exact role in protection from or pathogenesis of malaria is not yet well characterized.¹⁶⁹ The prevalence of aMBCs in the blood is associated with the level of parasite exposure¹⁷⁴ and decreases rapidly if parasite exposure is discontinued.¹⁷⁵ These cells are missing the classic surface markers of MBCs, CD21 and CD27, and express less IgG on their surface but instead express the inhibitory receptor FcRL5 and the transcription factor T-bet.¹⁶⁹ Interestingly, malaria-associated aMBCs show signs of hyperactivation and are resistant to further stimulation prompting some to propose that the expression of FcRL5 may be an attempt to downregulate this hyperactivation.¹⁷⁶ Compared with MBCs, these cells have been shown to have reduced B cell receptor signaling capacity, reduced proliferation and are deficient in secretion of protective antibodies.¹⁶⁹ The fact that aMBCs increase in frequency over time and exposure could suggest that their generation is a way for Plasmodium parasites to actively evade the adaptive immune system via immune dysregulation.¹⁶⁹

Contrary to early studies looking at total aMBCs, recent work by Hopp et al.¹⁷⁷ showed that P. falciparum antigen-specific aMBCs expand during acute malaria and although these cells are transcriptionally distinct at healthy baseline, they are transcriptionally similar to B cells after activation. Additionally, aMBCs were shown to express markers indicative of T cell interactions and to secrete IgG and IgM.¹⁷⁷ Taken together, this new work suggests that these cells may help rather than hinder the anti-malarial immune response and warrants further study.

Plasmodium dysregulation and evasion of the adaptive immune response

As an intracellular pathogen during most of its life cycle, Plasmodium evades some detection by the adaptive immune system simply by residing inside a host cell, particularly an RBC. Typically, intracellular pathogens are detected by CD8+ T cells, which recognize foreign antigens presented by MHC class I on the cell surface.¹³⁷ Because mature RBCs do not express MHC class I,⁸⁵ Plasmodium species that infect mature RBCs (e.g. P. falciparum) cannot be detected by the body’s classic anti-intracellular pathogen response. Inside the RBC, parasites are also protected from recognition by antibodies specific to antigens on the parasite surface that are not displayed on the RBC surface.⁸⁵

In addition to an intracellular niche, Plasmodium parasites evade the adaptive immune response via variant surface antigen (VSA) expression and active dysregulation of the immune response to render it inefficient.⁸⁵ These mechanisms have been most well-characterized for P. falciparum. Parasites decorate the surface of iRBCs with VSAs from large multigene families, and these surface antigens are the target of many anti-Plasmodium antibodies. However, extreme sequence variation both within and between parasite populations renders it nearly impossible to generate antibodies to all copies at once.⁸⁵ The VSA PfEMP1 is encoded by the var multi-gene family, which has approximately 60 antigenically distinct copies per parasite genome and is the most well-studied VSA.¹¹ P. falciparum also express VSAs from the RIFIN (repetitive interspersed families of polypeptide) and STEVOR (subtelomeric variant open reading frame) families, which are less well studied.⁸⁶ While individual parasites express only 1 copy of PfEMP1 at a time, they possess the ability to switch between copies during an infection, referred to as antigenic variation, allowing for effective evasion of any antibodies generated to the previous copy (Fig. 2A).⁸⁶ Additionally, parasites can generate new PfEMP1 sequences via nonhomologous recombination in the mosquito, leading to a near-infinite number of possible sequences that the immune system would need to recognize to provide sterile immunity to the parasites. Tissue sequestration is an additional immune evasion mechanism employed by the parasite wherein PfEMP1 and other VSAs bind to host endothelial receptors (EPCR, CD36, CSA, or intercellular adhesion molecules) to promote adherence and sequestration of iRBCs within the vasculature where they are protected from circulating immune cells and splenic clearance.¹¹ Interestingly, VSAs are also capable of rosetting, in which uninfected RBCs surround an iRBC and effectively hide the PfEMP1 molecule from circulating antibodies.⁸⁶ Taken together, parasitic expression of VSAs on the surface of iRBCs demonstrate several effective host immune evasion mechanisms.

Because DCs bridge the innate and adaptive immune systems, dysregulation of DCs can derail the entire adaptive immune response. In high transmission settings, Plasmodium infection has been associated with reduced DC activation, leading to impaired production of proinflammatory cytokines and T cell–activating cytokines such as IL-12, although the mechanism by which DC function is impaired is not yet known.⁶⁴ Moreover, the precise consequences of this reduction in DC activation is not yet clear, but it may contribute to the lack of development of long-term immunity, typically associated with memory adaptive cells to this parasite. PfEMP1 can bind to CD36 or CD51 on the surface of DCs, which reduces their ability to present antigens and secrete cytokines, rather than trigger phagocytosis and antigen processing, which are key to initiating the adaptive response,⁸⁶ potentially contributing to this dysregulation in the setting of P. falciparum infection (Fig. 2B). These dysregulated DCs also downregulate costimulatory molecules and secrete anti-inflammatory cytokines, further impairing their ability to initiate and/or actively suppressing an effective adaptive response.⁷⁴^,¹⁷⁸ In addition to diminished numbers and functional dysregulation, P. falciparum infection has been shown to increase the susceptibility of DCs to apoptosis, which is associated with increased levels of IL-10.⁷¹

Plasmodium parasites appear to evade T cell–mediated immunity by skewing T cell polarization toward subtypes that impair the immune response.¹³⁷ DCs with impaired activation and expression of costimulatory molecules, described previously, are less able to form stable interactions with T cells that would lead to their activation and proliferation.¹⁷⁸ This ultimately can impair T cell development toward an effective anti-malarial phenotype, as has been described for Tfh cells,¹⁷⁹ which are essential for the development of a B cell response.⁶⁴ Some studies have found stable interactions between DCs and T cells but described a skewed response toward a Th1 phenotype, rather than Tfh, contributing to an impaired humoral response.¹⁷⁸ Additionally, P. berghei has been shown to actively disrupt memory T cell development by secreting a cytokine-like molecule, Plasmodium macrophage migration inhibitory factor.¹⁸⁰ This Plasmodium cytokine induces release of inflammatory cytokines from macrophages and DCs, such as TNFα and IL-12, which skew antigen-specific T cell polarization toward a short-lived effector phenotype, rather than toward a memory phenotype (Fig. 2C).¹⁸⁰ Further studies of human-infecting parasites are needed to confirm whether Plasmodium macrophage migration inhibitory factor impacts memory T cell development in humans, as well.

In addition to impaired T cell help in the germinal center and antigenic variation, described previously, Plasmodium parasites may also directly dysregulate the B cell response to evade the humoral immune system. Similar to DCs, PfEMP1 can directly interact with B cells, which leads to a polyclonal, nonspecific expansion, rather than a productive, antigen-specific development.¹⁵⁵ Similar to T cells, Plasmodium infection can also lead to polarization of B cells away from an effective, long-lasting response. Plasmodium infection seems to disproportionately skew the humoral response toward short-lived plasmablast generation (Fig. 2D),¹³⁶ potentially via the highly proinflammatory environment that is characteristic of malaria.¹⁴ In addition to being short-lived, many of the plasmablasts induced during malaria are not specific to Plasmodium antigens,¹⁴ and these cells can act as a nutrient sink,¹³⁶ limiting the ability of GCBs to develop and mature into specific, long-lasting effector cells. The GCBs that do manage to develop into long-lasting MBCs often develop an atypical phenotype,¹⁷⁴ described in more detail previously, which may or may not lead to protection from subsequent Plasmodium challenges.

Summary and conclusion

The immune response to P. falciparum malaria is complex and both the innate and the adaptive immune system contribute to protection from disease, as well as the development of malaria symptoms, summarized in Table 1. Additionally, P. falciparum has evolved numerous ways to evade the human defenses during malaria that help to shape the immune response. Here, we reviewed the major cell types involved in the human immune response to P. falciparum blood-stage parasites and the P. falciparum evasion mechanisms used to escape immune clearance. Despite decades of progress summarized here, the mechanisms of both host defenses and pathogen immune evasion are still incompletely understood. Future work is critical to characterize how P. falciparum shapes the human immune response, and particularly how we can exploit this information to generate stronger, long-lasting immunity to these parasites.

Table 1.

Summary of host responses and P. falciparum immune evasion techniques.

Immune cell type	Host response	P. falciparum evasion
Innate immune system
Neutrophils	Phagocytosis of merozoites or iRBCs Antibody-dependent respiratory burst NET formation	Recruitment of C1-INH, factor H and plasminogen Surface antigenic variation Development within RBCs Rosette formation to avoid phagocytosis Tissue sequestration iRBC CD47 surface expression Hemozoin formation Dysregulation of DCs (mechanism still uncharacterized)
Monocytes/macrophages	Phagocytosis (opsonic or nonopsonic) of merozoites or iRBCs Release of proinflammatory cytokines
DCs	Bridge innate and adaptive response Phagocytosis of merozoites or iRBCs Prime T cell response in secondary lymphoid tissues
Adaptive immune system
NK cells (innate lymphoid cells)	Antibody-dependent cell-mediated cytotoxicity of iRBCs iRBC destruction via IFNγ production	Development within RBCs (no MHC class I expression) Surface antigenic variation Rosette formation to avoid antibody detection of surface antigens Impaired T cell activation via dysregulated DC response T cell polarization away from phenotypes conducive to clearing parasitemia and/or memory T cell formation Polarization of B cells away from an effective, long-lasting response
CD4+ T cells	Role depends on phenotype Activation of phagocytes via IFNγ production Reduction of immunopathology via IL-10 production B-cell support via IL-4 production
Tfh cells	Bridge cellular and humoral response Stimulate B cell maturation and survival in germinal centers Promote B cell–mediated generation of P. falciparum–specific antibodies
Tregs	Regulate inflammation via IL-10 production Antagonize control of parasitemia
γδ T cells	Proinflammatory cytokine production Cytotoxic granule release to inhibit parasite growth in iRBCs Merozoite destruction via IFNγ production
B cells	Generation and secretion of P. falciparum–specific antibodies Plasmablasts act as a nutrient sink Long-lived plasma cells continuously produce anti-Plasmodium antibodies
Memory T cells	Can expand quickly to provide a faster adaptive immune response upon rechallenge with P. falciparum Function depends on phenotype
Memory B cells	Can expand quickly upon rechallenge to produce anti-Plasmodium antibodies Can display exhausted phenotype (atypical memory B cells) with reduced B cell receptor signaling capacity

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Acknowledgments

We thank the funders of the work cited in the previous text for making this work possible and for members of the Serre Lab for supporting this manuscript.

Contributor Information

Kieran Tebben, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States.

Rosita Asawa, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States.

David Serre, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States.

Kirsten E Lyke, Malaria Research Program, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States.

Author contributions

Conceptualization: K.T., D.S., Methodology: K.T., D.S., Investigation: K.T., R.A., Visualization: R.A., Funding acquisition: D.S., Project administration: K.T., D.S., R.A., K.E.L., Supervision: D.S., K.E.L., Writing–original draft: K.T., R.A., Writing–review & editing: K.T., D.S., R.A., K.E.L.

K.T. (Conceptualization [Equal], Data curation [Equal], Writing—original draft [Equal], Writing—review & editing [Equal]), R.A. (Writing—original draft [Equal], Writing—review & editing [Equal]), D.S. (Funding acquisition [Lead], Resources [Equal], Writing—original draft [Equal], Writing—review & editing [Equal]), and K.E.L. (Supervision [Equal], Writing—review & editing [Equal])

Funding

This work was supported by National Institutes of Health grant R21AI146853.

Conflicts of interest

The authors have no conflicts of interest to declare.

Data availability

All information cited in the above text is from available published scientific literature.

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PERMALINK

Cellular and molecular interactions underlying the peripheral immune responses to blood-stage malaria infections

Kieran Tebben

Rosita Asawa

David Serre

Kirsten E Lyke

Roles

Abstract

Malaria

Immune responses to the P. falciparum IDC

Figure 1.

Figure 2.

Innate immune responses

Complement

Innate immune sensing of P. falciparum

Neutrophils

Monocytes and macrophages

Dendritic cells

NK cells

P. falciparum blood-stage evasion of the innate immune response

Adaptive immune responses to blood-stage Plasmodium parasites

CD4+ T helper cells

T follicular helper cells

Regulatory T cells

γδ T cells

B cells

Antibodies

Development of adaptive immune memory to blood-stage parasites

T cell–mediated memory

B cell–mediated memory

Atypical MBCs

Plasmodium dysregulation and evasion of the adaptive immune response

Summary and conclusion

Table 1.

Acknowledgments

Contributor Information

Author contributions

Funding

Conflicts of interest

Data availability

References

Associated Data

Data Availability Statement

ACTIONS

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RESOURCES

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