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

虽然IFN-alpha/beta在防御病毒感染中的作用已被充分证明，但IFN-lambda的重要性仍不太清楚。IFN-λ的受体主要在上皮细胞上表达，表明IFN-λ在处于持续病毒攻击下的粘膜表面赋予先天免疫。IFN-λ受体也在一些免疫细胞如B细胞和巨噬细胞上表达，但IFN-λ在获得性免疫中的重要性迄今尚未被彻底研究。我的小组最近的工作表明，在限制感染肠道上皮的病毒方面，IFN-λ比IFN-α/β重要得多，这表明IFN-λ在粘膜表面起着非冗余的作用。如果这种观点是正确的，那么IFN-λ在呼吸道病毒的防御中也应该发挥核心作用。我们最近的数据表明，当感染开始于上呼吸道时，情况可能确实如此。因此，IFN-λ在呼吸道先天免疫中的重要性在过去可能被低估了，主要是因为在实验性流感病毒感染期间通常绕过鼻粘膜屏障。我们计划巩固和扩展我们的初步结果，表明IFN-λ限制呼吸道病毒从上呼吸道到肺部的有效传播，并限制呼吸道病毒在小鼠中的传播。我们还将评估IL-22通过与IFN-λ协同作用帮助限制呼吸道病毒传播的可能性，如在肠道中观察到的轮状病毒。我们进一步假设IFN-λ可以在粘膜组织中形成适应性免疫。为此，我们将通过测量STAT转录因子的磷酸化和IFN应答基因的诱导来确定哪些免疫细胞亚群可以对IFN-λ应答。此外，我们将确定当疫苗应用于粘膜组织时，Ifnlr 1缺陷型小鼠的疫苗应答是否与野生型对照小鼠不同。总的来说，这个项目将有助于理解IFN-λ在先天性和适应性免疫中的重要性。

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.