干扰素诱导跨膜蛋白3差异性调控包膜病毒感染侵入的分子机制研究

干扰素诱导表达多种干扰素刺激基因在抗病毒固有免疫中发挥关键作用。既往研究发现干扰素诱导跨膜蛋白3（IFITM3）可抑制多种包膜病毒由内涵体或溶酶体膜侵入宿主细胞，提出“囊膜钢化”或胆固醇累积假说以解释IFITM3抑制病毒感染的机制。近期申请人首次发现IFITM3显著促进人冠状病毒OC43感染宿主细胞（PNAS，2014），同时发现IFITM3对拉沙病毒侵入没有抑制作用，提示IFITM3对包膜病毒侵入的调控具有选择性和差异性。前期工作发现，IFITM3与不同病毒受体的共定位和相互作用与IFITM3抑制病毒感染能力密切相关，因此申请人提出全新假说“IFITM3和病毒受体在内涵体或溶酶体膜相互作用精确调控病毒的感染性”。本研究将鉴定冠状病毒OC43的受体，进而研究IFITM3与对其敏感性不同的病毒受体的精确相互作用，揭示全新的IFITM3影响病毒侵入的机制，为深入抗病毒药物的研发提供新的依据。

Interferon-stimulated genes(ISGs) play pivotal roles in antiviral innate immunity. Interferon-induced transmembrane protein3 (IFITM3), restricts viral entry of many enveloped viruses in endosome, with proposed inhibitory mechanisms of "endosomal tough membrane" or "cholesterol accumulation". Our recent work published in PNAS demonstrated that IFITM3 promotes the entry of HCoV-OC43, but restricts SARS-CoV infection and has no inhibition effect of Lassa virus, indicating IFITM3 deferentially and selectively modulate the entry of enveloped viruses. Our pilot study also found the IFITM3-viral receptor interaction and co-localization is closely associated with IFITM3's inhibitory capacity. We thus proposed a new model "IFITM3 deferentially modulates a given virus entry into host cells by its delicate interactions with viral receptor". In this study, we are going to identify the HCoV-OC43 receptor and try to figure out the delicate interaction between IFITM3 and receptors of different viruses which have different susceptibility to IFITM's modulation. Our work would reveal novel mechanism of how IFITM3 control viral entry and expand our knowledge in development of novel antiviral therapeutics.