Phosphatidylinositol 3-kinase ? is required for the development of experimental cerebral malaria

Experimental cerebral malaria (ECM) is characterized by a strong immune response, with leukocyte recruitment, blood-brain barrier breakdown and hemorrhage in the central nervous system. Phosphatidylinositol 3-kinase ? (PI3Ky) is central in signaling diverse cellular functions. Using PI3Ky-deficient mice (PI3Ky_-/-) and a specific PI3Ky inhibitor, we investigated the relevance of PI3Ky for the outcome and the neuroinflammatory process triggered by Plasmodium berghei ANKA (PbA) infection. Infected PI3Ky_-/- mice had greater survival despite similar parasitemia levels in comparison with infected wild type mice. Histopathological analysis demonstrated reduced hemorrhage, leukocyte accumulation and vascular obstruction in the brain of infected PI3Ky_-/- mice. PI3Ky deficiency also presented lower microglial activation (Iba-1+ reactive microglia) and T cell cytotoxicity (Granzyme B expression) in the brain. Additionally, on day 6 post-infection, CD3₊CD8₊ T cells were significantly reduced in the brain of infected PI3Ky_-/- mice when compared to infected wild type mice. Furthermore, expression of CD44 in CD8+ T cell population in the brain tissue and levels of phospho-IkB-α in the whole brain were also markedly lower in infected PI3Ky_-/- mice when compared with infected wild type mice. Finally, AS605240, a specific PI3Ky inhibitor, significantly delayed lethality in infected wild type mice. In brief, our results indicate a pivotal role for PI3Ky in the pathogenesis of ECM.