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

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-alpha/beta) and type III (IFN-lambda) interferons. All nucleated cells are believed to respond to IFN-alpha/beta, whereas IFN-lambda 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-alpha/beta receptors. Accordingly, after oral infection of IFN-alpha/beta 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-lambda receptor-deficient mice, suggesting that the gut mucosa is equipped with a compartmentalized IFN system in which epithelial cells mainly respond to IFN-lambda that they produce after viral infection, whereas other cells of the gut mostly rely on IFN-alpha/beta for antiviral defense. In suckling mice with IFN-lambda receptor deficiency, reovirus replicated in the gut epithelium and additionally infected epithelial cells lining the bile ducts, indicating that infants may use IFN-lambda for the control of virus infections in various epithelia-rich tissues. Thus, IFN-lambda 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-alpha/beta system which would induce exacerbated inflammation.