Brain microvessel cross-presentation is a hallmark of experimental cerebral malaria

Authors

  • Shanshan W. Howland,

    1. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
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  • Chek Meng Poh,

    1. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
    2. Department of Microbiology, Life Sciences Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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  • Sin Yee Gun,

    1. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
    2. Department of Microbiology, Life Sciences Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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  • Carla Claser,

    1. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
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  • Benoit Malleret,

    1. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
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  • Nilabh Shastri,

    1. Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
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  • Florent Ginhoux,

    1. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
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  • Gijsbert M. Grotenbreg,

    1. Department of Microbiology, Life Sciences Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
    2. Faculty of Science, Department of Biological Sciences, Life Sciences Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
    3. Immunology Programme, Life Sciences Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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  • Laurent Rénia

    Corresponding author
    1. Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
    2. Department of Microbiology, Life Sciences Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Abstract

Cerebral malaria is a devastating complication of Plasmodium falciparum infection. Its pathogenesis is complex, involving both parasite- and immune-mediated events. CD8+ T cells play an effector role in murine experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA) infection. We have identified a highly immunogenic CD8 epitope in glideosome-associated protein 50 that is conserved across rodent malaria species. Epitope-specific CD8+ T cells are induced during PbA infection, migrating to the brain just before neurological signs manifest. They are functional, cytotoxic and can damage the blood–brain barrier in vivo. Such CD8+ T cells are also found in the brain during infection with parasite strains/species that do not induce neuropathology. We demonstrate here that PbA infection causes brain microvessels to cross-present parasite antigen, while non-ECM-causing parasites do not. Further, treatment with fast-acting anti-malarial drugs before the onset of ECM reduces parasite load and thus antigen presentation in the brain, preventing ECM death. Thus our data suggest that combined therapies targeting both the parasite and host antigen-presenting cells may improve the outcome of CM patients.

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