Role of IFN-lambda in host defense against respiratory virus infections

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While the role of IFN-alpha/beta in defense of viral infections is well documented, the importance of IFN-lambda remains less clear. The receptor for IFN-lambda is expressed predominantly on epithelial cells, indicating that IFN-lambda confers innate immunity at mucosal surfaces which are under constant virus attack. The IFN-lambda receptor is also expressed on some immune cells such as B cells and macrophages, but the importance of IFN-lambda in adaptive immunity has to date not been investigated thoroughly. Recent work from my group demonstrated that IFN-lambda is far more important than IFN-alpha/beta in restricting viruses which infect the gut epithelium, indicating that IFN-lambda plays a non-redundant role at mucosal surfaces. If this view was correct, IFN-lambda should also play a central role in the defense of respiratory viruses. Our recent data indicate this might indeed be the case when infections start in the upper respiratory tract. Thus, the importance of IFN-lambda in innate immunity of the respiratory tract has probably been underestimated in the past, mainly because the nasal mucosal barrier is usually bypassed during experimental influenza virus infections. We plan to consolidate and extend our preliminary results which indicate that IFN-lambda restricts the efficient spread of respiratory viruses from the upper respiratory tract to the lungs and limits transmission of respiratory viruses in mice. We will also evaluate the possibility that IL-22 helps limiting transmission of respiratory viruses by synergizing with IFN-lambda as observed for rotaviruses in the intestinal tract. We further hypothesize that IFN-lambda can shape adaptive immunity in mucosal tissues. To this end, we will determine which immune cell subsets can respond to IFN-lambda by measuring phosphorylation of STAT transcription factors and induction of IFN-response genes. Further, we will determine whether vaccine responses in Ifnlr1-deficient mice differ from those of wild-type controls when vaccines are applied to mucosal tissues. Overall, this project will help appreciating the importance of IFN-lambda in innate and adaptive immunity.