IFNγ诱导的溶酶体巯基还原酶抑制包膜病毒感染侵入分子机制研究

干扰素刺激基因（ISG）在抗病毒固有免疫发挥关键作用。 目前已发现多种抗病毒ISG，其作用靶点多位于病毒侵入后阶段（post-entry）。申请人在研究IFITM抑制病毒侵入的基础上（PNAS，2014），利用多种ISG诱导表达细胞模型及假病毒感染系统，寻找新的抗高致病性病毒ISG。 申请人发现一种定位于溶酶体的ISG，干扰素诱导的溶酶体巯基还原酶（GILT），抑制三种高致病性病毒SARS-CoV、 Ebola virus、以及Lassa virus的侵入；并发现其抗病毒谱与包膜病毒利用溶酶体侵入途径密切相关。因此，申请人提出：“GILT可能特异性抑制病毒经溶酶体途径侵入细胞”。本研究将对GILT的结构功能关系进行深入，揭示GILT抗病毒侵入作用，并将对其抗病毒谱进行鉴别。通过对GILT抗病毒侵入机制研究，将拓展固有免疫系统拮抗病毒感染机制的认识，为控制相关病毒感染提供新的作用靶点。

Interferon-stimulated genes(ISGs) play pivotal roles in antiviral innate immunity. Many antiviral ISGs have been identified, although the majority of them target the post-entry stage in virus replication. In the effort to investigate ISG (eg. IFITM) inhibiting viral entry, our recent work published in PNAS has developed a panel of pseudotyped viral systems to explore ISG function. Together with ISG inducible expression system, we currently find that GILT, a Gamma-interferon-inducible lysosomal thiol reductase, is another lysosome associated ISG, which can inhibit viral entry of SARS-CoV, Ebola virus and Lassa virus. Concerning that these viruses infect their host cells via lysosome membrane fusion with virus envelop, we thus proposed that GILT is a novel ISG specifically inhibiting enveloped virus entry in lysosome. In this study, we are going to reveal GILT antiviral activity, survey the profile of virus susceptible to GILT inhibition, elucidate the molecular mechanism of how GILT inhibit viral entry. Our work would disclose novel mechanism of how innate immunity control viral entry and expand our knowledge in development of novel antiviral therapeutics.