Role of Astrocyte Activation in Experimental Cerebral Malaria

Abstract

Abstract Cerebral malaria (CM) is a severe complication of Plasmodium falciparum (Pf) with a high lethality rate. Key features at the cellular and molecular level are endothelial cell (EC) activation, blood-brain barrier (BBB) dysfunction, pro-inflammatory cytokine signaling, and sequestration of infected red blood cells (iRBCs). While research on malaria as a peripheral infection is extensive, there is still much left to investigate in terms of its neuropathological progression. Astrocytes are cells that maintain the stability of the BBB, yet nothing is known about their role in maintaining the BBB during cerebral malaria. In the mouse model of experimental cerebral malaria (ECM), we have used flow cytometry to determine that astrocytes in the cerebellum and frontal cortex of mice infected with Plasmodium berghei ANKA (PbA) are both activated at 6 days PI, a time-point correlated with breakdown of the BBB. Furthermore, EphA2, a receptor tyrosine kinase, is upregulated in malaria and plays a critical role in BBB disruption. We show increases in EphA2 densities on astrocytes in ECM. The implications of these data for BBB disruption in cerebral malaria will be discussed.