新冠病毒感染致免疫抑制和代谢重构的分子机制研究和拮抗手段的研发

固有免疫抵御病毒入侵。COVID19的爆发意味着它成功地抑制了宿主固有免疫响应，逃逸了免疫监视。新冠病人频繁的腹泻、炎症因子激增同时意味着病毒感染患者的肠道菌群和免疫代谢也发生了异常。本项目拟探究新冠病毒削弱宿主固有免疫、致代谢变化和人体微生态异常的分子机制并寻找拮抗手段。目前已明确：1、COVID19-Plpro、YmdB以及N 蛋白强烈的抑制宿主固有免疫的功能。Plpro和YmdB的作用底物分别是IRF7和IKKε；目前我们已建立Plpro的抑制剂筛选体系。2、COVID19感染降低了患者血样外泌体中促炎因子蛋白的丰度，同时，血液代谢指标如烟酰胺腺嘌呤二核苷酸的含量出现下降而抑炎代谢产物次黄嘌呤则出现上升。3、患者肠道微生物菌群尤其是普氏菌、拟杆菌所占比例大幅降低。本项目的完成将拓宽现有的抗病毒固有免疫视角，加深对宿主-病毒间分子相互作用机制的理解，为长期抗疫提供理论基础和方法学。

Innate antiviral immunity remains as the first line of defense against virus invasion. The outbreak of COVID19 suggests that this RNA virus could successfully suppressed the host's innate antiviral immune response and escaped from immune surveillance. The frequent diarrhea and inflammatory factor surges in patients with COVID19 also indicates abnormalities in the intestinal flora and immune metabolism of patients with viral infections. This project intends to explore the molecular mechanism underlying COVID19 infection and evasion of the host's innate immunity, metabolic changes and human microecological abnormalities and meanwhile search for intervention strategies . Up to now, we have several lines of observations clear: 1. COVID19-Plpro, YmdB and N protein strongly inhibit the host's innate antiviral immunity. The possible substrates of Plpro and YmdB are IRF7 and IKKε respectively; Currently we have established a screening system for potential small molecule inhibitor of Plpro. 2. COVID19 infection reduces the abundance of proinflammatory factor proteins in blood samples of exosomes. At the same time, the content of blood metabolism such as nicotinamide adenine dinucleotide decreases while the anti-inflammatory metabolite hypoxanthine increases. Through a deep analysis of those parameters, we would be able to build a link between viral infection and metabolic disorders. 3. The proportion of patients' intestinal microbial flora, especially Przetella and Bacteroides, has been greatly reduced. Through more in-depth and targeted analysis of intestinal flora, we are expected to be able to reveal the molecular mechanism and regulation of human microecology participating in COVID19 infection. We believe that , upon successful completion of this project, we should not only broaden the existing anti-virus inherent immunity perspective, but also deepen the understanding of the host-virus molecular interaction mechanism, and meanwhile provide the theoretical basis and methodology for long-term anti-epidemic.