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

Norinne Lacerda-Queiroz, Fatima Brant, David Henrique Rodrigues, Juliana Priscila Vago, Milene Alvarenga Rachid, Lirlândia Pires Sousa, Mauro Martins Teixeira, Antonio Lucio Teixeira

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere119633
JournalPloS one
Volume10
Issue number3
DOIs
StatePublished - Mar 16 2015
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • General

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