CD8+ T Cells and IFN-γ Mediate the Time-Dependent Accumulation of Infected Red Blood Cells in Deep Organs during Experimental Cerebral Malaria

ABSTRACT Cerebral malaria is the most severe complication of human infection with Plasmodium falciparum. It was shown that Plasmodium berghei ANKA-induced cerebral malaria was prevented in 100% of mice depleted of CD8+ T cells 1 day prior to the development of neurological signs. However, the importance of parasites in the brains of these mice was never clearly investigated. Moreover, the relevance of this model to human cerebral malaria has been questioned many times, especially concerning the relative importance of leukocytes versus parasitized erythrocytes sequestered in the brain. Here, we show that mice protected from cerebral malaria by CD8+ T-cell depletion have significantly fewer parasites in the brain. Treatment of infected mice with an antimalarial drug 15 to 20 h prior to the estimated time of death also protected mice from cerebral malaria without altering the number of CD8+ T cells in the brain. These mice subsequently developed cerebral malaria with parasitized red blood cells in the brain. Our results clearly demonstrated that sequestration of CD8+ T cells in the brain is not sufficient for the development of cerebral malaria in C57BL/6 mice but that the concomitant presence of parasitized red blood cells is crucial for the onset of pathology. Importantly, these results also demonstrated that the experimental cerebral malaria model shares many features with human pathology and might be a relevant model to study its pathogenesis.

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CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽

10.1182/blood-2002-05-1493 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4253-4259 ◽

Cited By ~ 82

Author(s):

Elodie Belnoue ◽

Michèle Kayibanda ◽

Jean-Christophe Deschemin ◽

Mireille Viguier ◽

Matthias Mack ◽

...

Keyword(s):

T Cells ◽

Cerebral Malaria ◽

Cd8 T Cells ◽

Cytokine Production ◽

Wild Type ◽

Experimental Cerebral Malaria ◽

Pathologic Features ◽

Th1 Cytokine ◽

The Brain ◽

Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

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Establishment of a murine model of cerebral malaria in KunMing mice infected with Plasmodium berghei ANKA

Parasitology ◽

10.1017/s0031182016001475 ◽

2016 ◽

Vol 143 (12) ◽

pp. 1672-1680 ◽

Cited By ~ 2

Author(s):

YAN DING ◽

WENYUE XU ◽

TAOLI ZHOU ◽

TAIPING LIU ◽

HONG ZHENG ◽

...

Keyword(s):

Red Blood Cells ◽

Cerebral Malaria ◽

Plasmodium Berghei ◽

Blood Cells ◽

Mononuclear Cells ◽

Clinical Signs ◽

Necrosis Factor Alpha ◽

Experimental Cerebral Malaria ◽

Km Mice

SUMMARYMalaria remains one of the most devastating diseases. Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection resulting in high mortality and morbidity worldwide. Analysis of precise mechanisms of CM in humans is difficult for ethical reasons and animal models of CM have been employed to study malaria pathogenesis. Here, we describe a new experimental cerebral malaria (ECM) model with Plasmodium berghei ANKA infection in KunMing (KM) mice. KM mice developed ECM after blood-stage or sporozoites infection, and the development of ECM in KM mice has a dose-dependent relationship with sporozoites inoculums. Histopathological findings revealed important features associated with ECM, including accumulation of mononuclear cells and red blood cells in brain microvascular, and brain parenchymal haemorrhages. Blood–brain barrier (BBB) examination showed that BBB disruption was present in infected KM mice when displaying clinical signs of CM. In vivo bioluminescent imaging experiment indicated that parasitized red blood cells accumulated in most vital organs including heart, lung, spleen, kidney, liver and brain. The levels of inflammatory cytokines interferon-gamma, tumour necrosis factor-alpha, interleukin (IL)-17, IL-12, IL-6 and IL-10 were all remarkably increased in KM mice infected with P. berghei ANKA. This study indicates that P. berghei ANKA infection in KM mice can be used as ECM model to extend further research on genetic, pharmacological and vaccine studies of CM.

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IFN-γ–Producing CD4+ T Cells Promote Experimental Cerebral Malaria by Modulating CD8+ T Cell Accumulation within the Brain

The Journal of Immunology ◽

10.4049/jimmunol.1200688 ◽

2012 ◽

Vol 189 (2) ◽

pp. 968-979 ◽

Cited By ~ 106

Author(s):

Ana Villegas-Mendez ◽

Rachel Greig ◽

Tovah N. Shaw ◽

J. Brian de Souza ◽

Emily Gwyer Findlay ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cerebral Malaria ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

Experimental Cerebral Malaria ◽

Cell Accumulation ◽

Ifn Γ ◽

The Brain

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Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria

Infection and Immunity ◽

10.1128/iai.00985-16 ◽

2017 ◽

Vol 85 (5) ◽

Cited By ~ 22

Author(s):

Matthew A. Huggins ◽

Holly L. Johnson ◽

Fang Jin ◽

Aurelie N′Songo ◽

Lisa M. Hanson ◽

...

Keyword(s):

T Cells ◽

Cerebral Malaria ◽

Vascular Permeability ◽

Brain Edema ◽

Cd8 T Cells ◽

Large Scale ◽

Neurological Deficits ◽

Brain Swelling ◽

Experimental Cerebral Malaria ◽

Bbb Permeability

ABSTRACT Human cerebral malaria (HCM) is a serious complication of Plasmodium falciparum infection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale magnetic resonance imaging (MRI) study in humans identified brain swelling as the most prominent predictor of fatal HCM. Therefore, in this study, we sought to define the mechanism controlling brain edema through the use of the murine experimental cerebral malaria (ECM) model. Specifically, we investigated the ability of CD8 T cells to initiate brain edema during ECM. We determined that areas of blood-brain barrier (BBB) permeability colocalized with a reduction of the cerebral endothelial cell tight-junction proteins claudin-5 and occludin. Furthermore, through small-animal MRI, we analyzed edema and vascular leakage. Using gadolinium-enhanced T1-weighted MRI, we determined that vascular permeability is not homogeneous but rather confined to specific regions of the brain. Our findings show that BBB permeability was localized within the brainstem, olfactory bulb, and lateral ventricle. Concurrently with the initiation of vascular permeability, T2-weighted MRI revealed edema and brain swelling. Importantly, ablation of the cytolytic effector molecule perforin fully protected against vascular permeability and edema. Furthermore, perforin production specifically by CD8 T cells was required to cause fatal edema during ECM. We propose that CD8 T cells initiate BBB breakdown through perforin-mediated disruption of tight junctions. In turn, leakage from the vasculature into the parenchyma causes brain swelling and edema. This results in a breakdown of homeostatic maintenance that likely contributes to ECM pathology.

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γδ-T cells promote IFN-γ–dependent Plasmodium pathogenesis upon liver-stage infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814440116 ◽

2019 ◽

Vol 116 (20) ◽

pp. 9979-9988 ◽

Cited By ~ 10

Author(s):

Julie C. Ribot ◽

Rita Neres ◽

Vanessa Zuzarte-Luís ◽

Anita Q. Gomes ◽

Liliana Mancio-Silva ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cerebral Malaria ◽

Molecular Mechanisms ◽

Critical Role ◽

Γδ T Cells ◽

Experimental Cerebral Malaria ◽

Liver Stage ◽

Ifn Γ ◽

Stage Infection

Cerebral malaria (CM) is a major cause of death due to Plasmodium infection. Both parasite and host factors contribute to the onset of CM, but the precise cellular and molecular mechanisms that contribute to its pathogenesis remain poorly characterized. Unlike conventional αβ-T cells, previous studies on murine γδ-T cells failed to identify a nonredundant role for this T cell subset in experimental cerebral malaria (ECM). Here we show that mice lacking γδ-T cells are resistant to ECM when infected with Plasmodium berghei ANKA sporozoites, the liver-infective form of the parasite and the natural route of infection, in contrast with their susceptible phenotype if challenged with P. berghei ANKA-infected red blood cells that bypass the liver stage of infection. Strikingly, the presence of γδ-T cells enhanced the expression of Plasmodium immunogenic factors and exacerbated subsequent systemic and brain-infiltrating inflammatory αβ-T cell responses. These phenomena were dependent on the proinflammatory cytokine IFN-γ, which was required during liver stage for modulation of the parasite transcriptome, as well as for downstream immune-mediated pathology. Our work reveals an unanticipated critical role of γδ-T cells in the development of ECM upon Plasmodium liver-stage infection.

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IRGM3 Contributes to Immunopathology and Is Required for Differentiation of Antigen-Specific Effector CD8+T Cells in Experimental Cerebral Malaria

Infection and Immunity ◽

10.1128/iai.02701-14 ◽

2015 ◽

Vol 83 (4) ◽

pp. 1406-1417 ◽

Cited By ~ 5

Author(s):

Jintao Guo ◽

James A. McQuillan ◽

Belinda Yau ◽

Gregory S. Tullo ◽

Carole A. Long ◽

...

Keyword(s):

T Cells ◽

Cerebral Malaria ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Type I ◽

Experimental Cerebral Malaria ◽

Content Type ◽

Cytokines And Chemokines ◽

Specific Effector ◽

Ifn Γ

Gamma interferon (IFN-γ) drives antiparasite responses and immunopathology during infection withPlasmodiumspecies. Immunity-related GTPases (IRGs) are a class of IFN-γ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. However, it is currently unknown whether IRGs modulate responses during malaria. We have used thePlasmodium bergheiANKA (PbA) model in which mice develop experimental cerebral malaria (ECM) to study the roles of IRGM1 and IRGM3 in immunopathology. Induction of mRNA forIrgm1andIrgm3was found in the brains and spleens of infected mice at times of peak IFN-γ production.Irgm3−/−but notIrgm1−/−mice were completely protected from the development of ECM, and this protection was associated with the decreased induction of inflammatory cytokines, as well as decreased recruitment and activation of CD8+T cells within the brain. Although antigen-specific proliferation of transferred CD8+T cells was not diminished compared to that of wild-type recipients following PbA infection, T cells transferred intoIrgm3−/−recipients showed a striking impairment of effector differentiation. Decreased induction of several inflammatory cytokines and chemokines (interleukin-6, CCL2, CCL3, and CCL4), as well as enhanced mRNA expression of type-I IFNs, was found in the spleens ofIrgm3−/−mice at day 4 postinfection. Together, these data suggest that protection from ECM pathology inIrgm3−/−mice occurs due to impaired generation of CD8+effector function. This defect is nonintrinsic to CD8+T cells. Instead, diminished T cell responses most likely result from defective initiation of inflammatory responses in myeloid cells.

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