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

虽然干扰素-α/β在防御病毒感染中的作用已经得到了很好的证明，但干扰素-lambda的重要性仍然不太清楚。干扰素-lambda的受体主要表达在上皮细胞上，这表明干扰素-lambda在不断受到病毒攻击的粘膜表面具有天然免疫力。干扰素-lambda受体也表达在一些免疫细胞上，如B细胞和巨噬细胞，但迄今为止，干扰素-lambda在获得性免疫中的重要性尚未得到彻底的研究。我的团队最近的工作表明，在限制感染肠道上皮的病毒方面，干扰素-lambda比干扰素-α/β重要得多，这表明干扰素-lambda在粘膜表面发挥着非多余的作用。如果这一观点是正确的，干扰素-lambda也应该在防御呼吸道病毒方面发挥核心作用。我们最近的数据表明，当感染从上呼吸道开始时，情况可能确实如此。因此，干扰素-lambda在呼吸道天然免疫中的重要性过去可能被低估了，主要是因为在实验性流感病毒感染期间，鼻黏膜屏障通常被绕过。我们计划巩固和推广我们的初步结果，这些结果表明，干扰素-lambda可以限制呼吸道病毒从上呼吸道有效地传播到肺部，并限制呼吸道病毒在小鼠体内的传播。我们还将评估IL-22通过与肠道轮状病毒中观察到的干扰素-lambda协同作用来帮助限制呼吸道病毒传播的可能性。我们进一步假设，干扰素-lambda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干扰素反应基因的诱导来确定哪些免疫细胞亚群可以对干扰素-lambda做出反应。此外，我们将确定当疫苗应用于粘膜组织时，Ifnlr1缺陷小鼠的疫苗反应是否与野生型对照的不同。总体而言，该项目将有助于认识干扰素-lambda在先天免疫和获得性免疫中的重要性。

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.