Severe malaria is associated with parasite binding to endothelial protein C receptor

TY - JOUR

T1 - Severe malaria is associated with parasite binding to endothelial protein C receptor

AU - Turner, Louise

AU - Lavstsen, Thomas

AU - Berger, Sanne S

AU - Wang, Christian W

AU - Petersen, Jens E V

AU - Avril, Marion

AU - Brazier, Andrew J

AU - Freeth, Jim

AU - Jespersen, Jakob S

AU - Nielsen, Morten A

AU - Magistrado, Pamela

AU - Lusingu, John

AU - Smith, Joseph D

AU - Higgins, Matthew K

AU - Theander, Thor G

PY - 2013/6/27

Y1 - 2013/6/27

N2 - 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.

AB - 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.

KW - Animals

KW - Antigens, CD

KW - Blood Coagulation

KW - Brain

KW - CHO Cells

KW - Cell Adhesion

KW - Cell Line

KW - Cricetinae

KW - Endothelial Cells

KW - Erythrocyte Membrane

KW - Humans

KW - Inflammation

KW - Malaria, Falciparum

KW - Microcirculation

KW - Plasmodium falciparum

KW - Protozoan Proteins

KW - Receptors, Cell Surface

U2 - 10.1038/nature12216

DO - 10.1038/nature12216

M3 - Journal article

C2 - 23739325

SN - 0028-0836

VL - 498

SP - 502

EP - 505

JO - Nature

JF - Nature

IS - 7455

ER -