title: Chemotactic antiviral cytokines promote infectious apical entry of human adenovirus into polarized epithelial cells.
abstract: Mucosal epithelia provide strong barriers against pathogens. For instance, the outward facing apical membrane of polarized epithelial cells lacks receptors for agents, such as hepatitis C virus, herpesvirus, reovirus, poliovirus or adenovirus. In addition, macrophages eliminate pathogens from the luminal space. Here we show that human adenovirus type 5 engages an antiviral immune response to enter polarized epithelial cells. Blood-derived macrophages co-cultured apically on polarized epithelial cells facilitate epithelial infection. Infection also occurs in the absence of macrophages, if virus-conditioned macrophage-medium containing the chemotactic cytokine CXCL8 (interleukin-8), or recombinant CXCL8 are present. In polarized cells, CXCL8 activates a Src-family tyrosine kinase via the apical CXCR1 and CXCR2 receptors. This activation process relocates the viral co-receptor ανβ3 integrin to the apical surface, and enables apical binding and infection with adenovirus depending on the primary adenovirus receptor CAR. This paradigm may explain how other mucosal pathogens enter epithelial cells.
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors.forename: Verena
authors.initials: V
authors.lastname: Lütschg
authors.forename: Karin
authors.initials: K
authors.lastname: Boucke
authors.forename: Silvio
authors.initials: S
authors.lastname: Hemmi
authors.forename: Urs F
authors.initials: UF
authors.lastname: Greber
mesh_terms: D000260:Adenoviruses, Human / Q000276:immunology / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D004847:Epithelial Cells / Q000821:virology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016209:Interleukin-8 / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D018613:Microscopy, Confocal; D053586:Virus Internalization
chemical_list: D039302:Integrin alphaVbeta3; D016209:Interleukin-8