Cerebral malaria (CM) is the leading cause of death in children infected with Plasmodium falciparum. Approximately 20% of children admitted to hospital with CM will die. In the experimental cerebral malaria (ECM) in mice T cell trafficking to the brain is a central feature causing lethality of CM. When children are admitted to hospital with CM, preventing further T cell trafficking to the brain upon anti-malaria drug treatment and exacerbated of cerebral inflammation in response to necrotic iRBCs, may improve survival rates. Eph receptors are the largest family of receptor tyrosine kinases. They have been split into 2 groups based on sequence conservation- the A and B families- and these receptors bind ephrin A and B ligands, respectively. T cells express both EphB receptors and ephrin B ligands, with putative functions in T cell co-stimulation and trafficking. The long-term goal of this projec is to develop an adjunct therapy for CM based on the Eph /ephrin family of molecules. Our preliminary data suggests that the "B" family of Eph / ephrin molecules facilitate T cell traffickig to the brain during ECM and the objective of this proposal is to confirm this role for EphB receptors / ephrin B molecules in malaria infection. The central hypothesis of this proposal is that T cell expressed Ephrin B ligands mediate adhesion of T cells to EphB receptors upregulated in the microvasculature in response to inflammatory stimuli from iRBCs. The rationale for undertaking the work in this proposal is that molecules traditionally involved in T cell trafficking around the body, specifically P- and E- selectins, ICAM1 and VCAM1, bind to adhered malaria-infected red blood cells (iRBCs) as well as platelets activated during malaria infection, making these ligands unavailable for T cell binding and suggesting that there are other molecules that facilitate T cell adhesion in the brain. Guided by our preliminary data, this centra hypothesis will be tested by pursuing 3 specific aims: 1) Demonstrate role of ephrin B ligands / Eph B receptors in mediating T cell trafficking to the brain in ECM;2) Demonstrate the effect of malaria infection on ephrin-mediated T cell binding to brain microvascular endothelial cells;and 3) Quantify the adhesive properties of T cell-expressed ephrin B ligand and Eph B receptor molecules in malaria infection. The approach is innovative because no role for EphB receptors / ephrin B ligands has yet been proposed in malaria infection. The proposed research is significant because the molecules mediating T cell trafficking to the brain in CM are currently unknown and the identification of new targets for adjunct therapies for use in malaria infection is urgently needed.
The proposed research is relevant to public health because this is an exploratory project that could identify the ephrin ligands / Eph receptors as completely novel targets of an adjunct therapy to limit T cell trafficking to the brain during cerebral malari, in turn saving the lives of children with life- threatening symptoms of malaria infection. Thus the proposed research is relevant to the part of the NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human disease and disability.