Ssu72在高致病性禽流感病毒紊乱机体免疫系统导致细胞因子风暴的机制研究

高致病性H5N1、H7N9禽流感病毒感染可紊乱机体免疫系统造成细胞因子风暴，导致急性呼吸窘迫综合征，病死率高，但其致病机理尚未完全解析。申请人前期实验表明，禽流感病毒可以通过抑制宿主的Ssu72蛋白影响RNA聚合酶II，导致机体整体转录异常，发生双向转录产生大量非编码RNA。本项目将利用已建立的过表达/敲低Ssu72的细胞及Ssu72转基因小鼠模型，揭示Ssu72在禽流感病毒感染紊乱机体免疫系统、引发细胞因子风暴损伤机体过程中的关键作用。基于已有的禽流感病毒感染细胞、动物及临床患者血样来源的高通量转录组学测序数据，深入解析禽流感病毒通过Ssu72介导机体发生双向转录产生异常非编码RNA、紊乱NF-κB等重要免疫通路引发细胞因子风暴的分子机理。本研究将阐明并增加一条Ssu72介导的禽流感病毒紊乱机体免疫系统导致细胞因子风暴的新致病机理，为缓解禽流感造成的急性呼吸窘迫综合征提供潜在治疗靶点。

Highly pathogenic avian influenza H5N1, H7N9 virus could disturbance immune system and cause cytokine storm, inducing acute respiratory distress syndrome (ARDS), the mortality rates were high, but the pathogenic mechanism still not fully understand. Our previous results shown that the avian influenza virus could influence RNA polymerase II via inhibit the host’s Ssu72 protein, causing global transcription disturbance, occurred bi-directional transcription producing massive abnormal non-coding RNAs. This project will reveal the key role of Ssu72 among avian influenza virus disturbance immune system, causing cytokine storm and lung damage, using established over-expression/knock-down Ssu72 cells and Ssu72 transgenic mouse models. Based on high-throughput sequencing data from avian influenza virus infected cells, mouse lungs and the patients’ blood samples, deeply analyzes the molecular mechanism of avian influenza virus induced bi-directional transcription increasing massive abnormal non-coding RNAs via Ssu72, disturbing important immune system such as NF-κB pathway inducing cytokine storm. This study will clarify a new pathogenic mechanism of avian influenza virus disturbance immune system causing cytokine storm via Ssu72, and provides potential new therapeutic target for alleviating ARDS caused by avian influenza virus.