Abstract

Endothelial protein C receptor is shown to be the receptor for Plasmodium falciparum erythrocyte membrane protein 1 variants associated with severe malaria. Severe childhood malaria, still causing about a million deaths every year, is triggered by the binding of red blood cells infected with the parasite Plasmodium falciparum to the walls of the host's blood vessels. P. falciparum erythrocyte membrane protein 1 (PfEMP1) containing domain cassettes 8 and 13 is known to be associated with severe malaria, and here Thomas Lavstsen and colleagues identify the receptor for PfEMP1 as endothelial protein C receptor (EPCR), a protein involved in regulating blood coagulation and the inflammatory response. This work could help to explain why some episodes of malaria are life-threatening and involve severe inflammation and suggests a target for future antimalarials. Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year1. Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining2. Severe childhood malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3), but the endothelial receptor for parasites expressing these proteins was unknown4,5. Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C6, as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies, and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways, and has implications for understanding malaria pathology and the development of new malaria interventions.