title: Leukocyte-derived IFN-α/β and epithelial IFN-λ constitute a compartmentalized mucosal defense system that restricts enteric virus infections.
abstract: Epithelial cells are a major port of entry for many viruses, but the molecular networks which protect barrier surfaces against viral infections are incompletely understood. Viral infections induce simultaneous production of type I (IFN-α/β) and type III (IFN-λ) interferons. All nucleated cells are believed to respond to IFN-α/β, whereas IFN-λ responses are largely confined to epithelial cells. We observed that intestinal epithelial cells, unlike hematopoietic cells of this organ, express only very low levels of functional IFN-α/β receptors. Accordingly, after oral infection of IFN-α/β receptor-deficient mice, human reovirus type 3 specifically infected cells in the lamina propria but, strikingly, did not productively replicate in gut epithelial cells. By contrast, reovirus replicated almost exclusively in gut epithelial cells of IFN-λ receptor-deficient mice, suggesting that the gut mucosa is equipped with a compartmentalized IFN system in which epithelial cells mainly respond to IFN-λ that they produce after viral infection, whereas other cells of the gut mostly rely on IFN-α/β for antiviral defense. In suckling mice with IFN-λ receptor deficiency, reovirus replicated in the gut epithelium and additionally infected epithelial cells lining the bile ducts, indicating that infants may use IFN-λ for the control of virus infections in various epithelia-rich tissues. Thus, IFN-λ should be regarded as an autonomous virus defense system of the gut mucosa and other epithelial barriers that may have evolved to avoid unnecessarily frequent triggering of the IFN-α/β system which would induce exacerbated inflammation.
authors: Institute of Virology, University Medical Center Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany.
authors: Tanel
authors: T
authors: Mahlakõiv
authors: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany; International Max Planck Research School for Molecular and Cell Biology (IMPRS-MCB), Freiburg, Germany; Research Centre Immunology and Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre, Mainz, Germany.
authors: Pedro
authors: P
authors: Hernandez
authors: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany; International Max Planck Research School for Molecular and Cell Biology (IMPRS-MCB), Freiburg, Germany; Research Centre Immunology and Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre, Mainz, Germany.
authors: Konrad
authors: K
authors: Gronke
authors: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany; Research Centre Immunology and Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre, Mainz, Germany.
authors: Andreas
authors: A
authors: Diefenbach
authors: Institute of Virology, University Medical Center Freiburg, Freiburg, Germany.
authors: Peter
authors: P
authors: Staeheli
mesh_terms: D000818:Animals; D002469:Cell Separation; D004847:Epithelial Cells / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D016898:Interferon-alpha / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology*; D012089:Mammalian orthoreovirus 3 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012088:Reoviridae Infections / Q000276:immunology*
chemical_list: D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma