title: Plasmodium falciparum adhesion domains linked to severe malaria differ in blockade of endothelial protein C receptor.
abstract: Cytoadhesion of Plasmodium falciparum-infected erythrocytes to endothelial protein C receptor (EPCR) is associated with severe malaria. It has been postulated that parasite binding could exacerbate microvascular coagulation and endothelial dysfunction in cerebral malaria by impairing the protein C-EPCR interaction, but the extent of binding inhibition has not been fully determined. Here we expressed the cysteine-rich interdomain region (CIDRα1) domain from a variety of domain cassette (DC) 8 and DC13 P. falciparum erythrocyte membrane protein 1 proteins and show they interact in a distinct manner with EPCR resulting in weak, moderate and strong inhibition of the activated protein C (APC)-EPCR interaction. Overall, there was a positive correlation between CIDRα1-EPCR binding activity and APC blockade activity. In addition, our analysis from a combination of mutagenesis and blocking antibodies finds that an Arg81 (R81) in EPCR plays a pivotal role in CIDRα1 binding, but domains with weak and strong APC blockade activity were distinguished by their sensitivity to inhibition by anti-EPCR mAb 1535, implying subtle differences in their binding footprints. These data reveal a previously unknown functional heterogeneity in the interaction between P. falciparum and EPCR and have major implications for understanding the distinct clinical pathologies of cerebral malaria and developing new treatment strategies.
authors.affiliation: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA, USA.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Sampath
authors.affiliation: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA, USA.
authors.forename: Andrew Jay
authors.initials: AJ
authors.lastname: Brazier
authors.affiliation: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Avril
authors.affiliation: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Bernabeu
authors.affiliation: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vigdorovich
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA, USA.
authors.forename: Anjali
authors.initials: A
authors.lastname: Mascarenhas
authors.affiliation: Department of Medicine, Goa Medical College and Hospital, Bambolim, Goa, India.
authors.forename: Edwin
authors.initials: E
authors.lastname: Gomes
authors.affiliation: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA, USA.
authors.forename: D Noah
authors.initials: DN
authors.lastname: Sather
authors.affiliation: Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.affiliation: Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA, USA.|Department of Global Health, University of Washington, Seattle, WA, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Smith
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D016466:CHO Cells; D002448:Cell Adhesion; D003412:Cricetulus; D004252:DNA Mutational Analysis; D042783:Endothelial Cells / Q000502:physiology*; D000074283:Endothelial Protein C Receptor; D054884:Host-Pathogen Interactions; D006801:Humans; D008288:Malaria / Q000469:parasitology* / Q000473:pathology; D010963:Plasmodium falciparum / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; C085731:erythrocyte membrane protein 1, Plasmodium falciparum