title: Shed GP of Ebola virus triggers immune activation and increased vascular permeability.
abstract: During Ebola virus (EBOV) infection a significant amount of surface glycoprotein GP is shed from infected cells in a soluble form due to cleavage by cellular metalloprotease TACE. Shed GP and non-structural secreted glycoprotein sGP, both expressed from the same GP gene, have been detected in the blood of human patients and experimentally infected animals. In this study we demonstrate that shed GP could play a particular role during EBOV infection. In effect it binds and activates non-infected dendritic cells and macrophages inducing the secretion of pro- and anti-inflammatory cytokines (TNFα, IL1β, IL6, IL8, IL12p40, and IL1-RA, IL10). Activation of these cells by shed GP correlates with the increase in surface expression of co-stimulatory molecules CD40, CD80, CD83 and CD86. Contrary to shed GP, secreted sGP activates neither DC nor macrophages while it could bind DCs. In this study, we show that shed GP activity is likely mediated through cellular toll-like receptor 4 (TLR4) and is dependent on GP glycosylation. Treatment of cells with anti-TLR4 antibody completely abolishes shed GP-induced activation of cells. We also demonstrate that shed GP activity is negated upon addition of mannose-binding sera lectin MBL, a molecule known to interact with sugar arrays present on the surface of different microorganisms. Furthermore, we highlight the ability of shed GP to affect endothelial cell function both directly and indirectly, demonstrating the interplay between shed GP, systemic cytokine release and increased vascular permeability. In conclusion, shed GP released from virus-infected cells could activate non-infected DCs and macrophages causing the massive release of pro- and anti-inflammatory cytokines and effect vascular permeability. These activities could be at the heart of the excessive and dysregulated inflammatory host reactions to infection and thus contribute to high virus pathogenicity.
authors.affiliation: Molecular Basis of Viral Pathogenicity, CIRI, INSERM U1111- CNRS UMR5308, Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Escudero-Pérez
authors.affiliation: Molecular Basis of Viral Pathogenicity, CIRI, INSERM U1111- CNRS UMR5308, Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Valentina A
authors.initials: VA
authors.lastname: Volchkova
authors.affiliation: Molecular Basis of Viral Pathogenicity, CIRI, INSERM U1111- CNRS UMR5308, Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Dolnik
authors.affiliation: Molecular Basis of Viral Pathogenicity, CIRI, INSERM U1111- CNRS UMR5308, Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Philip
authors.initials: P
authors.lastname: Lawrence
authors.affiliation: Molecular Basis of Viral Pathogenicity, CIRI, INSERM U1111- CNRS UMR5308, Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, Lyon, France.
authors.forename: Viktor E
authors.initials: VE
authors.lastname: Volchkov
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology / Q000821:virology; D029043:Ebolavirus / Q000276:immunology*; D006168:Guinea Pigs; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology*; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D008562:Membrane Glycoproteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014764:Viral Proteins