自噬基因Epg5在诺如病毒感染过程中的作用

诺如病毒（NoV）感染是全球流行性肠胃炎爆发的最主要原因，严重危害人类健康，目前仍无有效治疗措施。细胞自噬是一种高度保守的由溶酶体介导的降解途径，自噬异常与多种人类疾病相关。Epg5是在秀丽线虫中发现的一个新的自噬基因，调节小鼠肺部的免疫稳态平衡，并且与人类多系统失调症Vici syndrome相关。我们最近的实验结果发现，Epg5基因敲除小鼠对慢性诺如病毒（MNV.CR6）的感染具有很好的抵抗性，此结果还未见报道。为了进一步研究Epg5在诺如病毒感染中的作用，在本项目中我们提出以下研究内容：1）Epg5缺失是否引起肠道炎症发生包括IFN-λ效应因子转录水平升高；2）Epg5是否通过作用于肠道表皮细胞包括簇细胞在病毒感染中起作用；3）肠道共生菌群平衡改变与MNoV发病机制的可能关系。我们预期该研究将揭示自噬基因Epg5在诺如病毒感染中的作用，期望能够揭示Epg5与诺如病毒病理发生的关系。

Norovirus (NoV) is the leading cause of epidemic acute gastroenteritis globally, especially causing high morbidity and mortality in children, the elderly and immunocompromised individuals. Currently, there are no licensed antiviral treatments or vaccines due in part to our incomplete understanding of NoV pathogenesis. Autophagy is an evolutionarily conserved lysosome-mediated degradation process. It acts as a cell survival mechanism in response to various metabolic stresses and functions as a quality control system by selectively removing unwanted proteins and organelles. Dysfunctional autophagy has been linked to the development of multiple diseases. Epg5 was first identified in C. elegans as an essential autophagy gene which functions in macrophages to regulate the lung homeostasis in mouse, and shown to be linked to the multisystem human Vici syndrome. In mouse model the role of EPG5 in physiological processes and diseases remains largely unknown. We recently surprisingly found that Epg5-/- mice are resistant to infection by persistent murine norovirus (MNV.CR6) which has not been reported. To further study the role of Epg5 in the MNV.CR6 infection, we proposed: 1) to study if Epg5 plays role in intestinal inflammation including IFN-λ response genes activation; 2) to seek for the role of Epg5 in Tuft cells and other intestinal epithelial cells to regulate MNV.CR6 infection; 3) to investigate the correlation of the effect of Epg5 deficiency on microbiota dysbiosis with MNoV pathogenesis. Our work will uncover the role of autophagy gene Epg5 in MNoV infection, provide new insights for potential clinical prevention and treatment for NoV infection.