Overriding the Immune Evasion Tactics of Coronavirus

项目摘要/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 一种病毒介导的、调节失调的免疫反应，与过度产生炎症有关 细胞因子，细胞因子释放综合征。在这项提案中，我们试图确定治疗方法和知识 冠状病毒将中和参与有效宿主的细胞因子信号通路的破坏 防守。 我们致力于利用通路抑制SARS-CoV-2感染的治疗药物的迫切需求 特定的报告细胞，以筛选恢复细胞因子信号的治疗活性化合物。我们的道路 特定的筛查是整个SBP倡议的一个组成部分，该倡议旨在开发限制严重新冠肺炎的治疗方法。我们的 筛选策略选择在阻断SARS的药理活性治疗药物库中确定的药物- 冠状病毒2型裂解复制。我们使用细胞因子途径报告器来检验这些化合物在SARS-CoV-2感染中的作用。 BSL3设备中的肺细胞系和人肺有机体。选定的候选人将接受分析，以确定 潜在的药物开发。 冠状病毒感染相关细胞因子调节防御机制的基础知识 限制了治疗和疫苗的合理设计。为了促进这方面的知识，我们将重点放在淋巴毒素-- β受体(LTβR)和疱疹病毒进入介体(HVEM，TNFRSF14)调节抗-HBs的途径 病毒细胞因子、干扰素和白介素1(IL1β)。LTβR和HVEM途径共同作用于 集成的动态平衡网络，既能抑制病毒复制，又能限制组织破坏性细胞因子。两个SARS- CoV-2蛋白、类木瓜蛋白酶(PLPro、NSP3)和NSP9靶向TRAF3中的新成分 控制核转录因子κB转录组的交互作用组。我们将确定这些组件在密钥中的角色 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。 这两个独立但相辅相成的目标将提供一个帮助解决SARS的机会- CoV-2大流行，并保护子孙后代。

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.