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

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Hernandez,  Pedro
Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg;
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;
Research Centre Immunology and Institute of medical microbiology and Hygiene, University of Mainz Medical Centre;

Gronke,  Konrad
Spemann Graduate School of Biology and Medicine (SGBM) Albert Ludwigs University Freiburg;
Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg;
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Mahlakoiv, T., Hernandez, P., Gronke, K., Diefenbach, A., & Staeheli, P. (2015). Leukocyte-Derived IFN-α/β and Epithelial IFN-λ Constitute a Compartmentalized Mucosal Defense System that Restricts Enteric Virus Infections. PLoS Pathogens, 11, e1004782. doi:doi: 10.1371/journal.ppat.1004782.


Cite as: http://hdl.handle.net/someHandle/test/escidoc:902527
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.