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Published on: May 16, 2013
Diverse functional outcomes of Plasmodium falciparum ligation of EPCR: potential implications for malarial
Mark R Gillrie1, Marion Avril2, Andrew J Brazier2
1Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
Abstract:
Plasmodium falciparum-infected erythrocytes (IRBC) expressing the domain cassettes (DC) 8 and 13 of the cytoadherent ligand P. falciparum erythrocyte membrane protein 1 adhere to the endothelial protein C receptor (EPCR). By interfering with EPCR anti-coagulant and pro-endothelial barrier functions, IRBC adhesion could promote coagulation and vascular permeability that contribute to the pathogenesis of cerebral malaria. In this study, we examined the adhesion of DC8- and DC13-expressing parasite lines to endothelial cells from different microvasculature, and the consequences of EPCR engagement on endothelial cell function. We found that IRBC from IT4var19 (DC8) and IT4var07 (DC13) parasite lines adhered to human brain, lung and dermal endothelial cells under shear stress. However, the relative contribution of EPCR to parasite cytoadherence on different types of endothelial cell varied. We also observed divergent functional outcomes for DC8 cysteine-rich interdomain region (CIDR)α1.1 and DC13 CIDRα1.4 domains. IT4var07 CIDRα1.4 inhibited generation of activated protein C (APC) on lung and dermal endothelial cells and blocked the APC-EPCR binding interaction on brain endothelial cells. IT4var19 CIDRα1.1 inhibited thrombin-induced endothelial barrier dysfunction in lung endothelial cells, whereas IT4var07 CIDRα1.4 inhibited the protective effect of APC on thrombin-induced permeability. Overall, these findings reveal a much greater complexity of how CIDRα1-expressing parasites may modulate malaria pathogenesis through EPCR adhesion.
Insights
Plasmodium falciparum parasites adhere to endothelial protein C receptor, impacting malaria pathogenesis. Different parasite domains differentially affect endothelial cell functions, revealing complex interactions in cerebral malaria.
Area of Science:
- Malariology
- Vascular Biology
- Cellular Adhesion
Background:
- Plasmodium falciparum-infected erythrocytes (IRBC) express PfEMP1 variants that bind to endothelial protein C receptor (EPCR).
- IRBC adhesion to EPCR may disrupt endothelial barrier function and promote coagulation, contributing to cerebral malaria pathogenesis.
- The specific roles of different PfEMP1 domain cassettes (DC) and their interactions with EPCR remain incompletely understood.
Purpose of the Study:
- To investigate the adhesion of DC8- and DC13-expressing IRBC to various endothelial cells.
- To determine the functional consequences of EPCR engagement by these IRBC variants.
- To elucidate the distinct roles of DC8 and DC13 cysteine-rich interdomain regions (CIDR) in modulating endothelial cell function and malaria pathogenesis.
Main Methods:
- Adhesion assays of DC8 (IT4var19) and DC13 (IT4var07) parasite lines to human brain, lung, and dermal endothelial cells under shear stress.
- Assessment of EPCR engagement effects on endothelial cell function, including activated protein C (APC) generation and thrombin-induced permeability.
- Analysis of specific CIDR domains (CIDRα1.1 and CIDRα1.4) for their functional impact on endothelial cells.
Main Results:
- IRBC expressing DC8 and DC13 adhered to brain, lung, and dermal endothelial cells, with varying reliance on EPCR.
- The DC13 CIDRα1.4 domain inhibited APC generation and blocked APC-EPCR binding in brain endothelial cells.
- The DC8 CIDRα1.1 domain protected lung endothelial cells from thrombin-induced barrier dysfunction, while DC13 CIDRα1.4 interfered with APC's protective effects.
Conclusions:
- Parasite binding to EPCR is complex and varies across endothelial cell types and parasite domains.
- Different CIDR domains exhibit distinct mechanisms in modulating endothelial cell functions, influencing malaria pathogenesis.
- These findings highlight the intricate ways Plasmodium falciparum parasites interact with the endothelium via EPCR to drive disease severity.
