Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

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-theta) in experimental CM development was examined. PKC theta-deficient mice are resistant to CM development. In the absence of PKC-theta, no neurologic sign of CM developed after blood stage PbA infection. Resistance of PKC-theta-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-theta. Resistant PKC-theta-deficient mice developed high parasitemia, and died at 3 weeks with severe anemia. Therefore, PKC-theta 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. (Am J Pathol 2011, 178:212-221; DOI: 10.1016/j.ajpath.2010.11.008)