EphA2 promotes the development of experimental cerebral malaria. (MPF7P.707)

Abstract

Abstract Cerebral malaria is a severe complication of infection with the Plasmodium falciparum parasite, yet the etiology of the disease is not fully understood. In the well-established Plasmodium berghei ANKA (PbANKA) mouse model of experimental cerebral malaria (ECM), sequestration of parasitized red blood cells (pRBCs) and CD8+ T cells in the brain microvasculature is required for ECM development. However, our understanding of the receptors involved in CD8+ T cell adherence to the brain endothelium during ECM is currently incomplete. We hypothesize that EphA2, a member of the Eph family of receptor tyrosine kinases, is involved in the sequestration of CD8+ T cells in the brain during ECM through its interactions with membrane-bound ephrin-A ligands on CD8+ T cells. Using the PbANKA model of ECM, we show that EphA2 is upregulated in the brains of mice six days post-infection at the onset of cerebral symptoms in a lymphotoxin-α dependent manner. Ephrin-A ligands are also upregulated on splenic T cells of mice infected with PbANKA three days post-infection prior to potential trafficking to the brain. Importantly, EphA2-/- mice show significant resistance to death from ECM compared to EphA2+/+ mice. Similar numbers of pRBCs accumulate in the brains of EphA2-/- and EphA2+/+ mice, but EphA2-/- mice have less CD8+ T cells in the brain six days post-infection correlating with improved survival. Our data demonstrates a novel potential role for the EphA2 receptor in the pathogenesis of ECM.