title: Severe malaria is associated with parasite binding to endothelial protein C receptor.
abstract: 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. Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining. 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 unknown. Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C, 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.
authors.affiliation: Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark. lturner@sund.ku.dk
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavstsen
authors.forename: Sanne S
authors.initials: SS
authors.lastname: Berger
authors.forename: Christian W
authors.initials: CW
authors.lastname: Wang
authors.forename: Jens E V
authors.initials: JE
authors.lastname: Petersen
authors.forename: Marion
authors.initials: M
authors.lastname: Avril
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brazier
authors.forename: Jim
authors.initials: J
authors.lastname: Freeth
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Jespersen
authors.forename: Morten A
authors.initials: MA
authors.lastname: Nielsen
authors.forename: Pamela
authors.initials: P
authors.lastname: Magistrado
authors.forename: John
authors.initials: J
authors.lastname: Lusingu
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Smith
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Higgins
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001777:Blood Coagulation; D001921:Brain / Q000098:blood supply; D016466:CHO Cells; D002448:Cell Adhesion; D002460:Cell Line; D006224:Cricetinae; D042783:Endothelial Cells / Q000378:metabolism; D000074283:Endothelial Protein C Receptor; D004910:Erythrocyte Membrane / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000469:parasitology / Q000473:pathology; D016778:Malaria, Falciparum / Q000150:complications / Q000469:parasitology* / Q000473:pathology*; D008833:Microcirculation; D010963:Plasmodium falciparum / Q000737:chemistry / Q000378:metabolism* / Q000472:pathogenicity; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface