Publicação
IFNAR1 Controls Progression to Cerebral Malaria in Children and CD8+ T Cell Brain Pathology in Plasmodium berghei-Infected Mice
| Resumo: | 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. |
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| Autores principais: | Ball, E. A. |
| Outros Autores: | Sambo, M. R.; Martins, M.; Trovoada, M. J.; Benchimol, C.; Costa, J.; Antunes Goncalves, L.; Coutinho, A.; Penha-Goncalves, C. |
| Assunto: | CD8+ T cells Cerebral malaria Experimental Cerebral malaria Genetic association IFNAR1 |
| Ano: | 2013 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Repositório do GIMM – Gulbenkian Institute for Molecular Medicine |
| Idioma: | inglês |
| Origem: | ARCA |
| Resumo: | 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. |
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