title: Protein kinase C-theta is required for development of experimental cerebral malaria.
abstract: Cerebral malaria is the most severe neurologic complication in children and young adults infected with Plasmodium falciparum. T-cell activation is required for development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (CM). To characterize the T-cell activation pathway involved, the role of protein kinase C-theta (PKC-θ) in experimental CM development was examined. PKC-θ-deficient mice are resistant to CM development. In the absence of PKC-θ, no neurologic sign of CM developed after blood stage PbA infection. Resistance of PKC-θ-deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and magnetic resonance angiography, whereas wild-type mice developed distinct microvascular pathology. Recruitment and activation of CD8(+) T cells, and ICAM-1 and CD69 expression were reduced in the brain of resistant mice; however, the pulmonary inflammation and edema associated with PbA infection were still present in the absence of functional PKC-θ. Resistant PKC-θ-deficient mice developed high parasitemia, and died at 3 weeks with severe anemia. Therefore, PKC-θ signaling is crucial for recruitment of CD8(+) T cells and development of brain microvascular pathology resulting in fatal experimental CM, and may represent a novel therapeutic target of CM.
authors.affiliation: University of Orléans and CNRS, Molecular Immunology and Embryology UMR6218, Orléans, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Fauconnier
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Bourigault
authors.forename: Sandra
authors.initials: S
authors.lastname: Meme
authors.forename: Frederic
authors.initials: F
authors.lastname: Szeremeta
authors.forename: Jennifer
authors.initials: J
authors.lastname: Palomo
authors.forename: Adeline
authors.initials: A
authors.lastname: Danneels
authors.forename: Sabine
authors.initials: S
authors.lastname: Charron
authors.forename: Lizette
authors.initials: L
authors.lastname: Fick
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Beloeil
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Valerie F J
authors.initials: VF
authors.lastname: Quesniaux
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000469:parasitology / Q000473:pathology; D002545:Brain Ischemia / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D004195:Disease Models, Animal; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D018810:Magnetic Resonance Angiography; D008279:Magnetic Resonance Imaging; D016779:Malaria, Cerebral / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008833:Microcirculation; D055806:Microvessels / Q000473:pathology; D018512:Parasitemia / Q000201:enzymology / Q000276:immunology; D010962:Plasmodium berghei; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D000074121:Protein Kinase C-theta
chemical_list: D007527:Isoenzymes; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta