title: Modification of the cytoprotective protein C pathway during Dengue virus infection of human endothelial vascular cells.
abstract: Dengue fever (DF) is the most prevalent arthropod-borne viral disease of humans. No safe vaccine is available, there is no experimental animal model and no specific treatment (antiviral) for Dengue virus (DV) infection exists. The pathogenic mechanisms of the severe forms of the disease, such as Dengue shock syndrome (DSS) and Dengue haemorrhagic fever (DHF), in which endothelial damage is the pathognomonic sign, are not fully understood. Clinical observations have revealed significant abnormalities in the coagulation and inflammation systems, with increased levels of soluble thrombomodulin (sTM) in the plasma of patients with DHF/DSS (grade III or IV). Blood sTM was proposed as an early predictor of DSS during the febrile stage. However, the role of the DV in endothelial injury during DSS is unclear. Here, we present novel insights into the participation of DV in the downregulation of the thrombomodulin-thrombin-protein C complex formation at the endothelial surface, with a reduction in activated protein C (APC). APC is the most important vasoprotective protein because it downregulates thrombin generation (by the inactivation of procoagulant factors Va and VIIIa) and has anti-inflammatory, antiapoptotic, and barrier protection properties. These biological functions of APC are associated with the endothelial protein C receptor (EPCR) and protease-activated receptor 1 (PAR-1) signalling pathways, which link the coagulation-inflammation responses. We found alterations in the antithrombotic and cytoprotective protein C pathways during DV infection of human endothelial vascular cells, which may explain the vasculopathy observed during DHF/DSS. Clarification of the basic principles that underlie these processes has important implications for the design of new therapeutic strategies for DHF/DSS.
authors.affiliation: Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Apartado Postal 04510, México, DF, Mexico.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cabello-Gutiérrez
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Manjarrez-Zavala
authors.forename: Alejandra
authors.initials: A
authors.lastname: Huerta-Zepeda
authors.forename: Jorge
authors.initials: J
authors.lastname: Cime-Castillo
authors.forename: Verónica
authors.initials: V
authors.lastname: Monroy-Martínez
authors.forename: Benjamín Biruete-
authors.initials: BB
authors.lastname: Correa
authors.forename: Blanca H
authors.initials: BH
authors.lastname: Ruiz-Ordaz
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D002199:Capillary Permeability; D002460:Cell Line; D002522:Chlorocebus aethiops; D019610:Cytoprotection; D003716:Dengue Virus / Q000472:pathogenicity*; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D000074283:Endothelial Protein C Receptor; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D011486:Protein C / Q000378:metabolism*; D044463:Receptor, PAR-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D019595:Severe Dengue / Q000097:blood / Q000473:pathology / Q000821:virology*; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism*; D018180:Thrombomodulin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C508606:CXCL8 protein, human; D000074283:Endothelial Protein C Receptor; D018836:Inflammation Mediators; D016209:Interleukin-8; C478370:PROCR protein, human; D011486:Protein C; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin