IFN-κ抗呼吸道RNA病毒机制与应用研究

高致病性呼吸道RNA病毒感染如流感与冠状病毒等疫情频发且危害严重，研制广谱抗呼吸道RNA病毒的药物具有重要的现实意义。本团队前期研究表明：H9N2轻症较H7N9重症感染能更早地诱导I类IFN成员IFN-κ。与IFN-a和b通过STAT1抑制流感不同，IFN-κ主要通过MAPK通路上调cFos-CHD6通路而抑制流感病毒复制。在利用IFN-κ雾化吸入干预COVID-19临床研究中观察到，受试者肺部炎症消退与病毒核酸转阴的时间均比常规治疗组缩短，提示IFN-κ可抑制新冠病毒复制而诱导炎症较低，这与IFN-a诱导较高炎症显著不同，表明IFN-κ在抗RNA病毒上有独特的作用机制。本课题拟通过Gain-与Loss-of-function实验，系统解析IFN-κ作用于SARS-CoV-2的分子机制。预期结果有助于深入理解IFN-κ抑制RNA病毒共性机制，为开发广谱抗呼吸道RNA病毒药物提供理论基础。

Infections caused by highly pathogenic respiratory RNA viruses such as influenza and coronavirus have been a frequent and serious threat to human health, and thus it is of great practical significance to develop broad-spectrum antivirals against respiratory RNA viruses. Previous research by our team identified IFN-κ as a unique member of type I interferons induced by a non-pathogenic H9N2 virus but not the disease-causing 2013 H7N9 virus. Unlike IFN-α and β, which inhibit influenza through STAT1, IFN-κ exerts its anti-influenza activity primarily via upregulation of the MAPK-cFos-CHD6 axis. In clinical studies using IFN-κ to intervene in COVID-19 infection by aerosol inhalation, significant less time was taken to attain amelioration of lung inflammation and clearance of virus nucleic acid in IFN-κ–treated patients than the conventional treatment group. This observation clearly indicates that IFN-κ is effective in inhibiting COVID-19 without induction of high level of inflammation, which has been a well-known side-effect of IFN-a/β treatment, supporting that IFN-κ has a unique mechanism of action against RNA viruses. In this project, we proposes to systematically investigate the molecular mechanism of IFN-k acting on SARS-CoV-2 through both gain- and loss-of-function approaches. The results are expected to help gain a deep understanding of the general mechanism by which IFN-κ inhibits RNA viruses, and provide a new theoretical basis for efficacious treatment of respiratory RNA virus-causing diseases without the side effects.