title: Effects of Ebola virus glycoproteins on endothelial cell activation and barrier function.
abstract: Ebola virus causes severe hemorrhagic fever with high mortality rates in humans and nonhuman primates. Vascular instability and dysregulation are disease-decisive symptoms during severe infection. While the transmembrane glycoprotein GP(1,2) has been shown to cause endothelial cell destruction, the role of the soluble glycoproteins in pathogenesis is largely unknown; however, they are hypothesized to be of biological relevance in terms of target cell activation and/or increase of endothelial permeability. Here we show that virus-like particles (VLPs) consisting of the Ebola virus matrix protein VP40 and GP(1,2) were able to activate endothelial cells and induce a decrease in barrier function as determined by impedance spectroscopy and hydraulic conductivity measurements. In contrast, the soluble glycoproteins sGP and delta-peptide did not activate endothelial cells or change the endothelial barrier function. The VLP-induced decrease in barrier function was further enhanced by the cytokine tumor necrosis factor alpha (TNF-alpha), which is known to induce a long-lasting decrease in endothelial cell barrier function and is hypothesized to play a key role in Ebola virus pathogenesis. Surprisingly, sGP, but not delta-peptide, induced a recovery of endothelial barrier function following treatment with TNF-alpha. Our results demonstrate that Ebola virus GP(1,2) in its particle-associated form mediates endothelial cell activation and a decrease in endothelial cell barrier function. Furthermore, sGP, the major soluble glycoprotein of Ebola virus, seems to possess an anti-inflammatory role by protecting the endothelial cell barrier function.
authors.affiliation: Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Wahl-Jensen
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Afanasieva
authors.forename: Jochen
authors.initials: J
authors.lastname: Seebach
authors.forename: Ute
authors.initials: U
authors.lastname: Ströher
authors.forename: Heinz
authors.initials: H
authors.lastname: Feldmann
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schnittler
mesh_terms: D002478:Cells, Cultured; D019040:E-Selectin / Q000235:genetics; D029043:Ebolavirus / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism*; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D014771:Virion / Q000502:physiology
chemical_list: D019040:E-Selectin; D006023:Glycoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D017361:Viral Nonstructural Proteins; D018799:Intercellular Adhesion Molecule-1