Overriding the Immune Evasion Tactics of Coronavirus

项目总结/摘要 SARS-冠状病毒-2（SARS-CoV-2）感染患者进展为危及生命的疾病可能是由于 一种病毒介导的、失调的免疫反应，与过度产生炎性 细胞因子，细胞因子释放综合征。在这项提案中，我们寻求确定治疗方法和知识， 冠状病毒，将抵消干扰细胞因子信号通路参与有效宿主 防御 我们致力于迫切需要抑制SARS-CoV-2感染的治疗方法， 特异性报告细胞来筛选恢复细胞因子信号传导的治疗活性化合物。我们的道路 特定筛查是SBP范围内开发限制严重COVID-19治疗方法的一个组成部分。我们 筛选策略选择在阻断SARS的抗病毒治疗药物库中鉴定的药物， CoV-2裂解性复制。我们使用细胞因子途径报告基因来测试这些化合物在SARS-CoV-2感染中的作用， BSL 3设施中的肺细胞系和人肺类器官。被选中的候选人将接受分析， 潜在的药物开发 与冠状病毒感染相关的尼古丁调节防御机制的基础知识 限制了治疗和疫苗的合理设计。为了推进这方面的知识，我们专注于光合作用- β受体（LTβR）和疱疹病毒进入介质（HVEM，TNFRSF 14）通路已知调节抗- 病毒细胞因子、干扰素（IFN）和白细胞介素-1（IL 1 β）。LTβR和HVEM通路共同发挥作用， 整合的稳态网络，抑制病毒复制，但限制组织损伤细胞因子。两次SARS- CoV-2蛋白、木瓜蛋白酶样蛋白酶（PLPro，Nsp 3）和Nsp 9靶向TRAF 3中的新组分。 控制NFκB转录组相互作用体。我们将确定这些组件在关键 在小鼠冠状病毒肺部感染模型中使用遗传学和药理学方法的细胞因子途径。 这两个独立但互补的目标将为帮助解决SARS提供机会- CoV-2大流行，保护后代。

PROJECT SUMMARY/ABSTRACT Progression of SARS-Coronavirus-2 (SARS-CoV-2) infected patients to life threatening disease may result from a virus-mediated, dysregulated immune response associated with excessive production of inflammatory cytokines, cytokine release syndrome. In this proposal we seek to identify therapeutics and knowledge of Coronaviruses that will counteract the disruption in cytokine signaling pathways involved in effective host defense. We contribute to the urgent need for therapeutics that inhibit SARS-CoV-2 infection using pathway specific reporter cells to screen for therapeutically active compounds that restore cytokine signaling. Our pathway specific screens are a component in SBP-wide initiative to develop therapeutics that limit severe COVID-19. Our screening strategy selects drugs identified in libraries of pharmacologically active therapeutics that block SARS- CoV-2 lytic replication. We use cytokine pathway reporters to test these compounds in SARS-CoV-2 infection of a lung cell line and human lung organoids in BSL3 facilities. The selected candidates will undergo analysis for potential drug development. Fundamental knowledge of cytokine-regulated defense mechanisms related to Coronavirus infection limits the rational design of therapeutics and vaccines. To advance this knowledge we focus on the Lymphotoxin- β Receptor (LTβR) and the Herpesvirus entry mediator (HVEM, TNFRSF14) pathways known to regulate anti- viral cytokines, interferons (IFN) and interleukin-1(IL1β). Together, the LTβR and HVEM pathways act as an integrated, homeostatic network that inhibits virus replication yet limits tissue damaging cytokines. Two SARS- CoV-2 proteins, the Papain-like protease (PLPro, Nsp3) and Nsp9 target novel components in the TRAF3 interactome that control the NFκB transcriptome. We will determine the role of these components in the key cytokine pathways using genetic and pharmacologic approaches in a mouse coronavirus lung infection model. Together these two independent but complementary aims will provide an opportunity to help solve the SARS- CoV-2 pandemic, and protect future generations.