Leukocyte-Derived IFN-α/β and Epithelial IFN-λ Constitute a Compartmentalized Mucosal Defense System that Restricts Enteric Virus Infections

• Published in: PLoS pathogens Vol. 11; no. 4; p. e1004782
• Main Authors: Mahlakõiv, Tanel, Hernandez, Pedro, Gronke, Konrad, Diefenbach, Andreas, Staeheli, Peter
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2015; Public Library of Science (PLoS)
• Subjects: Animals; Cell Separation; Epithelial Cells - immunology; Flow Cytometry; Humans; Immunohistochemistry; Interferon-alpha - immunology; Interferon-beta - immunology; Interferon-gamma - immunology; Intestinal Mucosa - immunology; Leukocytes - immunology; Mammalian orthoreovirus 3 - immunology; Mice; Mice, Knockout; Polymerase Chain Reaction; Reoviridae Infections - immunology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1004782

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.