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

PLoS Pathog. 2015 Apr 7;11(4):e1004782. doi: 10.1371/journal.ppat.1004782. eCollection 2015 Apr.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Interferon-alpha
  • Interferon-beta
  • Interferon-gamma

Grant support

This study was supported in part by the Excellence Initiative of the German Federal and State Governments (GSC-4, Spemann Graduate School) and the Deutsche Forschungsgemeinschaft (SFB 620). (http://www.dfg.de). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.