title: Protein C system defects inflicted by the malaria parasite protein PfEMP1 can be overcome by a soluble EPCR variant.
abstract: 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.
authors.affiliation: Jens E. V. Petersen, Centre for Medical Parasitology, Dept. of International Health, Immunology & Microbiology, University of Copenhagen and Dept. of Infectious Diseases, Rigshospitalet, 1014 Copenhagen, Denmark, Tel.: +45 35327549, Fax: +45 35327851, E-mail: jevang@sund.ku.dk.
authors.forename: Jens E V
authors.initials: JE
authors.lastname: Petersen
authors.forename: Eveline A M
authors.initials: EA
authors.lastname: Bouwens
authors.forename: Ibai
authors.initials: I
authors.lastname: Tamayo
authors.forename: Louise
authors.initials: L
authors.lastname: Turner
authors.forename: Christian W
authors.initials: CW
authors.lastname: Wang
authors.forename: Monique
authors.initials: M
authors.lastname: Stins
authors.forename: Thor G
authors.initials: TG
authors.lastname: Theander
authors.forename: José
authors.initials: J
authors.lastname: Hermida
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Mosnier
authors.forename: Thomas
authors.initials: T
authors.lastname: Lavstsen
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000469:parasitology / Q000502:physiology*; D000074283:Endothelial Protein C Receptor; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology / Q000503:physiopathology*; D050505:Mutant Proteins / Q000008:administration & dosage; D010963:Plasmodium falciparum / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects; D011486:Protein C / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D044463:Receptor, PAR-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D050505:Mutant Proteins; C478370:PROCR protein, human; D011486:Protein C; D015800:Protozoan Proteins; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; C085731:erythrocyte membrane protein 1, Plasmodium falciparum
keywords: Malaria; PfEMP1; endothelial cells; endothelial protein C receptor