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 (CIDR?1) 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 CIDR?1-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 CIDR?1 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.

SUBMITTER: Sampath S 

PROVIDER: S-EPMC4661071 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature