SS7-3 A non-redundant role of IFN-λ in antiviral defense of the intestinal tract

Virus-infected cells secrete a broad range of interferon (IFN) subtypes which in turn trigger the synthesis of antiviral factors that confer host resistance. IFN-α, IFN-β and other type I IFNs signal through a common universally expressed cell surface receptor (IFNAR), whereas type III IFN (IFN-λ) uses a distinct cell-type-specific receptor complex (IL28R) for signaling. Using mice that lack functional receptors for IFNAR, IL28R, or both, we have recently shown that IFN-λ contributes to resistance against several human pathogenic viruses that infect the respiratory tract such as influenza A virus, respiratory syncytial virus and SARS coronavirus (Mordstein et al., J Virol 2010). We now present data indicating that IFN-λ also plays an important role in defense against viruses that infect the intestinal tract. Cells expressing functional IL28R complexes could be visualized throughout the entire intestinal tract. Interestingly, expression of interferon-induced Mx1 protein in these cells was much stronger after treatment with IFN-λ as compared to treatment with type I IFN. Intestinal epithelial cells (IEC) isolated from mice infected with murine rotavirus expressed antiviral genes only at low levels if IFN-λ signaling was impaired. In contrast, antiviral gene expression in IECs of IFNAR-deficient mice was only slightly lower than in cells from wild-type mice. Accordingly, significantly higher levels of murine rotavirus antigen could be detected in the colon of infected IL28R-deficient mice compared to wild-type mice or mice lacking functional type I IFN receptors. Together with our previous findings that functional IFN-λ signaling prevents spread of intranasally applied SARS coronavirus into the mouse intestine as well as virus shedding via the fecal route, our new data strongly suggest that IFN-λ plays a more prominent role in protection of the intestinal tract against viral infections than type I IFN.