戊型肝炎病毒通过激活宿主转录因子STAT3磷酸化促进其复制的分子机制研究

病毒与宿主间相互作用的动态过程决定病程的发生发展和抗病毒疗效。宿主信号转导和转录激活因子3（STAT3）参与调控宿主的多种生理或病理性过程，但其在戊型肝炎病毒（HEV）感染过程中的作用尚无研究。申请人对临床确诊的21位戊型肝炎病人肝脏组织样本分析发现，高达86%的病人肝脏组织中STAT3发生磷酸化。在体外细胞感染模型中，HEV亦能激活STAT3磷酸化，并促进病毒复制。利用小分子药物特异性阻断STAT3磷酸化可有效抑制HEV复制。为解析HEV激活STAT3发生磷酸化的分子机制，以及STAT3发生磷酸化后促进HEV复制的机理，本项目将整合申请人在HEV领域的研究积累，利用体外细胞模型及3D类器官模型探究HEV与STAT3相互作用的机制，并筛选特异性STAT3磷酸化抑制剂作为潜在抗HEV药物。该项目是在综合临床研究和实验室数据的基础上提出的，对深入解析HEV发病机理、发掘潜在抗病毒靶点至关重要。

The dynamic virus-host interaction largely determines the disease severity and the antiviral efficacy. Signal transducer and activator of transcription 3 (STAT3), as a key host factor, is centrally involved in diverse physiological or pathological processes. However, its potential function in the setting of hepatitis E virus (HEV) infection has not been studied yet. Therefore, the level of phosphorylated-STAT3 was assessed in paraffin-embedded liver tissues collected from 21 hepatitis E patients. Strikingly, up to 86% of patients showed positive staining of P-STAT3, while no staining was observed in negative controls. In vitro study also indicated that HEV could potently activate STAT3 phosphorylation and promote virus replication. Additionally. the specific inhibitor of STAT3 can effectively inhibit HEV replication in 5 different cell lines. Based on these inspiring results already obtained, the applicant will dissect the interaction between HEV and STAT3 and screen novel STAT3 inhibitors as potential antivirals by using state-of-art in vitro cell models and 3D organoid models. This project is proposed on the basis of comprehensive preclinical research and laboratory data, thus the knowledge gained will be essential for the understanding of HEV-related pathogenesis and the discovery of potential antiviral targets.