Effects of Ebola virus glycoproteins on endothelial cell activation and barrier function.
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.
Wahl-Jensen
Victoria M
VM
Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba.
Afanasieva
Tatiana A
TA
Seebach
Jochen
J
Ströher
Ute
U
Feldmann
Heinz
H
Schnittler
Hans-Joachim
HJ
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
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