EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria.

Author summary Malaria is a disease caused by transmission of the mosquito-borne Plasmodium parasite that remains a severe global public health issue. Advancements in parasite control measures such as prevention, treatment, and surveillance have reduced the incidence of malaria worldwide. However, current reports indicate that progress towards reducing global malaria cases and deaths in recent years has stalled. Therefore, it is imperative that we continue to explore new therapeutic avenues that can synergize with existing treatment methods. In particular, there is currently no adjunctive treatment available for cerebral malaria which is a serious complication of Plasmodium infection characterized by blood-brain barrier breakdown. Here, we have identified that a receptor EphA2 is required for the breakdown of the blood-brain barrier during Plasmodium infection in mice. We found that expression of this receptor is critical for inducing brain inflammation, recruiting immune cells to the brain, and disruption brain endothelial cell junctions. Inhibiting activation of this receptor using two different treatment approaches also prevented blood-brain barrier breakdown in mice. Thus, along with identifying a new molecule critical for cerebral malaria in mice we also provide a basis for exploring this receptor as a novel therapeutic target in human cerebral malaria in the future. Disruption of blood-brain barrier (BBB) function is a key feature of cerebral malaria. Increased barrier permeability occurs due to disassembly of tight and adherens junctions between endothelial cells, yet the mechanisms governing junction disassembly and vascular permeability during cerebral malaria remain poorly characterized. We found that EphA2 is a principal receptor tyrosine kinase mediating BBB breakdown during Plasmodium infection. Upregulated on brain microvascular endothelial cells in response to inflammatory cytokines, EphA2 is required for the loss of junction proteins on mouse and human brain microvascular endothelial cells. Furthermore, EphA2 is necessary for CD8+ T cell brain infiltration and subsequent BBB breakdown in a mouse model of cerebral malaria. Blocking EphA2 protects against BBB breakdown highlighting EphA2 as a potential therapeutic target for cerebral malaria.