Severe malaria is associated with parasite binding to endothelial protein C receptor
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Severe malaria is associated with parasite binding to endothelial protein C receptor. / Turner, Louise; Lavstsen, Thomas; Berger, Sanne S; Wang, Christian W; Petersen, Jens E V; Avril, Marion; Brazier, Andrew J; Freeth, Jim; Jespersen, Jakob S; Nielsen, Morten A; Magistrado, Pamela; Lusingu, John; Smith, Joseph D; Higgins, Matthew K; Theander, Thor G.
In: Nature, Vol. 498, No. 7455, 27.06.2013, p. 502-5.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 498
SP - 502
EP - 505
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7455
ER -
ID: 47523163