Project Summary/Abstract Malaria afflicts several hundred million and kills more than 600,000 people each year, mostly children in Sub-Saharan Africa. Plasmodium falciparum causes nearly all the malaria deaths. The most dreaded P. falciparum complication, cerebral malaria, is often fatal despite antimalarial treatment. Cerebral malaria (CM) is a cerebrovascular disease. Parasitized red blood cells (RBCs) sequester in the small vessels and can cause microvascular obstruction. While this mechanical plugging of vessels is thought to contribute to disease, endothelial dysfunction is proposed to play a major role. Pathologically, redistribution of tight junction proteins is observed in association with blood-brain barrier leakage. Nearly a decade ago, it was observed that P. falciparum-infected RBCs placed on an in vitro endothelial barrier caused increased permeability across the monolayer. We have discovered that this effect is due to export of the parasite- produced protein histidine-rich protein II (HRPII). HRPII binds to endothelial cells and triggers the inflammasome, resulting in endothelium junctional protein redistribution and barrier disruption. In vivo, HRPII causes increased blood-brain barrier permeability and leads to increased mortality in murine models of cerebral malaria. Unanswered questions are: how does HRPII bind to the endothelial surface? How does HRPII trigger the inflammasome? Can we block the effects of this toxin pharmacologically? To address these questions, aim 1 will identify endothelial HRPII receptor and inflammasome initiation mechanism. Both candidate gene and unbiased approaches will be tried. Aim 2 will focus on identification of therapeutic strategies for amelioration of cerebral malaria. We will test existing drugs against the inflammasome pathway as well as endothelial barrier-stabilizing drugs, using our mouse assays for HRPII action. We anticipate that the proposed studies will yield great insight into the pathogenesis of cerebral malaria and will point the way to new therapies to mitigate the devastating complications of falciparum malaria infections.