Pathogenic CD8+ T cells in experimental cerebral malaria

Howland, Shanshan W.; Claser, Carla; Poh, Chek Meng; Gun, Sin Yee; Rénia, Laurent

doi:10.1007/s00281-015-0476-6

Cited by 84 publications

(132 citation statements)

References 86 publications

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“…CD8 + T cells have been shown to play a major role in promoting death in ECM (16), and Gln metabolism is critical for the differentiation, proliferation, and function of effector T cells. Thus, we determined the effect of DON treatment on T cells in the brains of infected mice.…”

Section: Don Treatment Results In a Reduction In The Number Of Cd8mentioning

confidence: 99%

“…The development of ECM has been shown to be dependent on degranulation and perforin release of CD8 + T cells that accumulate in the brains of PbA-infected mice (16). Degranulation of CD8 + T cells results in the expression of CD107 on their plasma membranes.…”

Section: Don Treatment Results In a Reduction In The Number Of Cd8mentioning

confidence: 99%

“…On the other hand, CD8 + effector T cells that release perforin have been shown to play a critical role in promoting the pathogenesis that constitutes ECM (16). CD8 + T-cell activation results in a dramatic shift from oxidative metabolism to aerobic glycolysis and glutaminolysis necessary for T-cell expansion and effector function (18)(19)(20).…”

Section: Discussionmentioning

confidence: 99%

“…+ T cells are the major mediators of death in ECM (16) and that antigen-specific CD8 + T cells engage parasite antigens cross-presented on MHC class I molecules on brain endothelium, resulting in endothelial cell dysfunction by a perforin-dependent mechanism (17).…”

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confidence: 99%

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Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

Gordon

Hart

Tran

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The most deadly complication of Plasmodium falciparum infection is cerebral malaria (CM) with a case fatality rate of 15-25% in African children despite effective antimalarial chemotherapy. There are no adjunctive treatments for CM, so there is an urgent need to identify new targets for therapy. Here we show that the glutamine analog 6-diazo-5-oxo-L-norleucine (DON) rescues mice from CM when administered late in the infection a time at which mice already are suffering blood-brain barrier dysfunction, brain swelling, and hemorrhaging accompanied by accumulation of parasite-specific CD8 + effector T cells and infected red blood cells in the brain. Remarkably, within hours of DON treatment mice showed blood-brain barrier integrity, reduced brain swelling, decreased function of activated effector CD8 + T cells in the brain, and levels of brain metabolites that resembled those in uninfected mice. These results suggest DON as a strong candidate for an effective adjunctive therapy for CM in African children.cerebral malaria | adjunctive therapy | CD8 + T cells | glutamine metabolism | DON

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Section: Don Treatment Results In a Reduction In The Number Of Cd8mentioning

confidence: 99%

Section: Don Treatment Results In a Reduction In The Number Of Cd8mentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

Gordon

Hart

Tran

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…T cells have been shown to accumulate in the brain and to contribute to endothelial injury and death associated with ECM (54). PbA-infected miR-155 -/-mice had decreased GZMA mRNA (a tryptase contained in cytotoxic CD8 + T cells that induces cell death) levels in the brain.…”

Section: Resultsmentioning

confidence: 99%

miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria

Barker

Kim

et al. 2017

Mol Med

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miR-155 has been shown to participate in host response to infection and neuroinflammation via negative regulation of blood-brain barrier (BBB) integrity and T cell function. We hypothesized that miR-155 may contribute to the pathogenesis of cerebral malaria (CM). To test this hypothesis, we used a genetic approach to modulate miR-155 expression in an experimental model of cerebral malaria (ECM). In addition, an engineered endothelialized microvessel system and serum samples from Ugandan children with CM were used to examine anti-miR-155 as a potential adjunctive therapeutic for severe malaria. Despite higher parasitemia, survival was significantly improved in miR-155 -/-mice versus wild-type littermate mice in ECM. Improved survival was associated with preservation of BBB integrity and reduced endothelial activation, despite increased levels of proinflammatory cytokines. Pretreatment with antagomir-155 reduced vascular leak induced by human CM sera in an ex vivo endothelial microvessel model. These data provide evidence supporting a mechanistic role for miR-155 in host response to malaria via regulation of endothelial activation, microvascular leak and BBB dysfunction in CM.

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