Protein C system defects inflicted by the malaria parasite protein PfEMP1 can be overcome by a soluble EPCR variant
| Autor: | Louise Turner, Thor G. Theander, Monique F. Stins, José Hermida, Eveline A. Bouwens, Ibai Tamayo, Christian W. Wang, Thomas Lavstsen, Laurent O. Mosnier, Jens E.V. Petersen |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Plasmodium falciparum Protozoan Proteins Receptors Cell Surface Plasma protein binding 030204 cardiovascular system & hematology Article Pathogenesis 03 medical and health sciences 0302 clinical medicine Antigens CD parasitic diseases medicine Humans Receptor PAR-1 Cells Cultured Endothelial protein C receptor biology Brain Endothelial Cells Endothelial Protein C Receptor Hematology biology.organism_classification Cytoprotection Cell biology Malaria Protein Structure Tertiary 030104 developmental biology Cerebral Malaria Mutant Proteins Signal transduction Protein C medicine.drug Protein Binding Signal Transduction |
| Zdroj: | Thromb Haemost |
| Popis: | SummaryThe Endothelial Protein C receptor (EPCR) is essential for the anticoagulant and cytoprotective functions of the Protein C (PC) system. Selected variants of the malaria parasite protein, Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) associated with severe malaria, including cerebral malaria, specifically target EPCR on vascular endothelial cells. Here, we examine the cellular response to PfEMP1 engagement to elucidate its role in malaria pathogenesis. Binding of the CIDRα1.1 domain of PfEMP1 to EPCR obstructed activated PC (APC) binding to EPCR and induced a loss of cellular EPCR functions. CIDRα1.1 severely impaired endothelial PC activation and effectively blocked APC-mediated activation of protease-activated receptor-1 (PAR1) and associated barrier protective effects of APC on endothelial cells. A soluble EPCR variant (E86A-sEPCR) bound CIDRα1.1 with high affinity and did not interfere with (A)PC binding to cellular EPCR. E86A-sEPCR used as a decoy to capture PfEMP1, permitted normal PC activation on endothelial cells, normal barrier protective effects of APC, and greatly reduced cytoadhesion of infected erythrocytes to brain endothelial cells. These data imply important contributions of PfEMP1-induced protein C pathway defects in the pathogenesis of severe malaria. Furthermore, the E86A-sEPCR decoy provides a proof-of-principle strategy for the development of novel adjunct therapies for severe malaria. |
| Databáze: | OpenAIRE |
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