title: Phosphatidylinositol 3-Kinase γ is required for the development of experimental cerebral malaria.
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 γ (PI3Kγ) is central in signaling diverse cellular functions. Using PI3Kγ-deficient mice (PI3Kγ-/-) and a specific PI3Kγ inhibitor, we investigated the relevance of PI3Kγ for the outcome and the neuroinflammatory process triggered by Plasmodium berghei ANKA (PbA) infection. Infected PI3Kγ-/- 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 PI3Kγ-/- mice. PI3Kγ 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 PI3Kγ-/- 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 PI3Kγ-/- mice when compared with infected wild type mice. Finally, AS605240, a specific PI3Kγ inhibitor, significantly delayed lethality in infected wild type mice. In brief, our results indicate a pivotal role for PI3Kγ in the pathogenesis of ECM.
authors.affiliation: Laboratory of Immunopharmacology/Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Norinne
authors.initials: N
authors.lastname: Lacerda-Queiroz
authors.affiliation: Laboratory of Immunopharmacology/Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Fatima
authors.initials: F
authors.lastname: Brant
authors.affiliation: Laboratory of Immunopharmacology/Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: David Henrique
authors.initials: DH
authors.lastname: Rodrigues
authors.affiliation: Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Juliana Priscila
authors.initials: JP
authors.lastname: Vago
authors.affiliation: Laboratory of Immunopharmacology/Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Milene Alvarenga
authors.initials: MA
authors.lastname: Rachid
authors.affiliation: Laboratory of Immunopharmacology/Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Lirlândia Pires
authors.initials: LP
authors.lastname: Sousa
authors.affiliation: Laboratory of Immunopharmacology/Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Minas Gerais, Brazil.
authors.forename: Mauro Martins
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: Laboratory of Immunopharmacology/Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil; Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Minas Gerais, Brazil.
authors.forename: Antonio Lucio
authors.initials: AL
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000276:immunology / Q000469:parasitology; D005260:Female; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000469:parasitology; D016779:Malaria, Cerebral / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology / Q000473:pathology*; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010962:Plasmodium berghei / Q000276:immunology*; D011810:Quinoxalines / Q000494:pharmacology; D016019:Survival Analysis; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse