title: Crimean-Congo hemorrhagic fever virus activates endothelial cells.
abstract: Crimean-Congo hemorrhagic fever virus (CCHFV) causes viral hemorrhagic fever with high case-fatality rates and is geographically widely distributed. Due to the requirement for a biosafety level 4 (BSL-4) laboratory and the lack of an animal model, knowledge of the viral pathogenesis is limited. Crimean-Congo hemorrhagic fever (CCHF) is characterized by hemorrhage and vascular permeability, indicating the involvement of endothelial cells (ECs). The interplay between ECs and CCHFV is therefore important for understanding the pathogenesis of CCHF. In a previous study, we found that CCHFV-infected monocyte-derived dendritic cells (moDCs) activated ECs; however, the direct effect of CCHFV on ECs was not investigated. Here, we report that ECs are activated upon infection, as demonstrated by upregulation of mRNA levels for E-selectin, vascular cell adhesion molecule 1 (VCAM1), and intercellular adhesion molecule 1 (ICAM1). Protein levels and cell surface expression of ICAM1 responded in a dose-dependent manner to increasing CCHFV titers with concomitant increase in leukocyte adhesion. Furthermore, we examined vascular endothelial (VE) cadherin in CCHFV-infected ECs by different approaches. Infected ECs released higher levels of interleukin 6 (IL-6) and IL-8; however, stimulation of resting ECs with supernatants derived from infected ECs did not result in increased ICAM1 expression. Interestingly, the moDC-mediated activation of ECs was abrogated by addition of neutralizing tumor necrosis factor alpha (TNF-α) antibody to moDC supernatants, thereby identifying this soluble mediator as the key cytokine causing EC activation. We conclude that CCHFV can exert both direct and indirect effects on ECs.
authors.affiliation: KCB/Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Connolly-Andersen
authors.forename: Guido
authors.initials: G
authors.lastname: Moll
authors.forename: Cecilia
authors.initials: C
authors.lastname: Andersson
authors.forename: Sara
authors.initials: S
authors.lastname: Akerström
authors.forename: Helen
authors.initials: H
authors.lastname: Karlberg
authors.forename: Iyadh
authors.initials: I
authors.lastname: Douagi
authors.forename: Ali
authors.initials: A
authors.lastname: Mirazimi
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D003225:Hemorrhagic Fever Virus, Crimean-Congo / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016133:Polymerase Chain Reaction; D014709:Vero Cells; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D018799:Intercellular Adhesion Molecule-1; D000099152:Cadherin 5