title: Brain microvessel cross-presentation is a hallmark of experimental cerebral malaria.
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.
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research A*STAR, Singapore, Singapore.
authors.forename: Shanshan W
authors.initials: SW
authors.lastname: Howland
authors.forename: Chek Meng
authors.initials: CM
authors.lastname: Poh
authors.forename: Sin Yee
authors.initials: SY
authors.lastname: Gun
authors.forename: Carla
authors.initials: C
authors.lastname: Claser
authors.forename: Benoit
authors.initials: B
authors.lastname: Malleret
authors.forename: Nilabh
authors.initials: N
authors.lastname: Shastri
authors.forename: Florent
authors.initials: F
authors.lastname: Ginhoux
authors.forename: Gijsbert M
authors.initials: GM
authors.lastname: Grotenbreg
authors.forename: Laurent
authors.initials: L
authors.lastname: Rénia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000032:analysis / Q000276:immunology*; D000962:Antimalarials / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D001921:Brain / Q000098:blood supply* / Q000276:immunology / Q000469:parasitology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000469:parasitology; D045142:Cross-Priming / Q000187:drug effects; D005260:Female; D006801:Humans; D016779:Malaria, Cerebral / Q000188:drug therapy / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D008969:Molecular Sequence Data; D059208:Parasite Load; D010962:Plasmodium berghei / Q000187:drug effects / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D000962:Antimalarials; D016693:Receptors, Antigen, T-Cell, alpha-beta; C113249:T cell receptor peptide Vbeta8.1
keywords: T cells; brain; cross-presentation; malaria; pathology