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

IFN-lambda 在宿主防御呼吸道病毒感染中的作用

基本信息

批准号：
317170439
负责人：
Professor Dr. Peter Stäheli
金额：
--
依托单位：
Institut für Medizinische Mikrobiologie und Hygiene (IMMH)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/317170439?language=en
关键词：
Role IFN lambda host defense

项目摘要

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.

虽然 IFN-α/β 在防御病毒感染中的作用已得到充分证明，但 IFN-lambda 的重要性仍不清楚。 IFN-lambda 的受体主要在上皮细胞上表达，表明 IFN-lambda 在持续受到病毒攻击的粘膜表面赋予先天免疫力。 IFN-lambda 受体也在一些免疫细胞（如 B 细胞和巨噬细胞）上表达，但 IFN-lambda 在适应性免疫中的重要性迄今为止尚未得到彻底研究。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，IFN-lambda 比 IFN-α/β 重要得多，这表明 IFN-lambda 在粘膜表面发挥着非冗余的作用。如果这个观点是正确的，那么 IFN-lambda 也应该在呼吸道病毒的防御中发挥核心作用。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，IFN-lambda在呼吸道先天免疫中的重要性在过去可能被低估，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，这些结果表明 IFN-lambda 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-lambda 协同作用（正如在肠道轮状病毒中观察到的那样）帮助限制呼吸道病毒传播的可能性。我们进一步假设 IFN-lambda 可以塑造粘膜组织的适应性免疫。为此，我们将通过测量 STAT 转录因子的磷酸化和 IFN 反应基因的诱导来确定哪些免疫细胞亚群可以对 IFN-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不同。总体而言，该项目将有助于认识 IFN-lambda 在先天性和适应性免疫中的重要性。