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Thromb Haemost 2015; 114(05): 1038-1048
DOI: 10.1160/TH15-01-0018
Blood Cells, Inflammation and Infection
Schattauer GmbH

Protein C system defects inflicted by the malaria parasite protein PfEMP1 can be overcome by a soluble EPCR variant

Jens E. V. Petersen
1   Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
,
Eveline A. M. Bouwens
2   Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
,
Ibai Tamayo
3   Thrombosis and Haemostasis Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
,
Louise Turner
1   Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
,
Christian W. Wang
1   Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
,
Monique Stins
4   Department of Neurology, Division NeuroImmunology, Johns Hopkins SOM and Department Molecular biology and Immunology, Malaria Research Institute, Bloomberg SPH, Baltimore, Maryland, USA
,
Thor G. Theander
1   Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
,
José Hermida   §
3   Thrombosis and Haemostasis Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
,
Laurent O. Mosnier   §
2   Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
,
Thomas Lavstsen   §
1   Centre for Medical Parasitology, Department of International Health, Immunology & Microbiology, University of Copenhagen and Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark
› Author Affiliations
Further Information

Publication History

Received: 09 January 2015

Accepted after major revision: 23 May 2015

Publication Date:
06 December 2017 (online)

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Summary

The 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.

Keywords

Malaria - endothelial cells - endothelial protein C receptor - PfEMP1

§ These authors contributed equally to the work.


 

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