title: IFNAR1 controls progression to cerebral malaria in children and CD8+ T cell brain pathology in Plasmodium berghei-infected mice.
abstract: Development of cerebral malaria (CM), a severe and fatal form of clinical Plasmodium falciparum infection, results from a damaging cascade of vascular, inflammatory, and immunological host responses that leads to brain injury. Progression to CM can be modified by host genetic factors. Our case-control study in Angolan children aimed at highlighting the role of IFN (α, β) receptor 1 (IFNAR1) in progression to CM. We report a robust association between IFNAR1 and CM protection, as well as detailed studies showing analogous protection from experimental CM in Ifnar1(-/-) mice infected with P. berghei ANKA. We developed a novel cell-transfer protocol that enables spleen cell priming in the absence of disease. This led to the discovery that IFNAR1 expression in CD8(+) T cells is crucial and can abrogate resistance to experimental CM in Ifnar1(-/-) mice. Splenic CD8(+) T cells from Ifnar1(-/-) mice are functionally activated upon infection, yet are unable to mediate experimental CM development within the brain tissue. Our findings prove that IFNAR1 signaling unleashes CD8(+) T cell effector capacity, which is vital for CM, and raises the hypothesis that the cohesive role of IFNAR1 in both human and mouse CM operates through CD8(+) T cell triggering.
authors.affiliation: Instituto Gulbenkian de Ciência, 2781-156 Oeiras, Portugal.
authors.forename: Elizabeth Ann
authors.initials: EA
authors.lastname: Ball
authors.forename: Maria Rosário
authors.initials: MR
authors.lastname: Sambo
authors.forename: Madalena
authors.initials: M
authors.lastname: Martins
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Trovoada
authors.forename: Carla
authors.initials: C
authors.lastname: Benchimol
authors.forename: João
authors.initials: J
authors.lastname: Costa
authors.forename: Lígia
authors.initials: L
authors.lastname: Antunes Gonçalves
authors.forename: António
authors.initials: A
authors.lastname: Coutinho
authors.forename: Carlos
authors.initials: C
authors.lastname: Penha-Gonçalves
mesh_terms: D000293:Adolescent; D000818:Animals; D001921:Brain / Q000276:immunology; D001927:Brain Diseases / Q000276:immunology / Q000469:parasitology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000469:parasitology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000276:immunology; D016779:Malaria, Cerebral / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010962:Plasmodium berghei / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000276:immunology
chemical_list: C508032:Ifnar1 protein, mouse; D053633:Receptor, Interferon alpha-beta