Louise Turner 1 , Thomas Lavstsen 1 , Sanne S. Berger 1 , Christian W. Wang 1 , Jens E.V. Petersen 1 , Marion Avril 2 , Andrew J. Brazier 2 , Jim Freeth 3 , Jakob S. Jespersen 1 , Morten A. Nielsen 1 , Pamela Magistrado 4 , John Lusingu 4 , Joseph D. Smith 2 , 5 , Matthew K. Higgins 6 , Thor G. Theander 1
05 June 2013
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 year 1 . Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining 2 . Severe malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DC) 8 and 13 3 , but the endothelial receptor for parasites expressing these proteins was unknown 4, 5 . Here, we identify endothelial protein C receptor (EPCR), which mediates cytoprotective effects of activated protein C 6 , as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the N-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.