Regulation of inflammatory gene expression during SARS2 infection

项目摘要 感染引起炎症，这有助于病原体清除和宿主的存活 有机体然而，未能调节炎症反应通常可导致多器官 对宿主的伤害和杀伤力。在当前由严重急性肺炎引起的COVID-19大流行中， 呼吸综合征冠状病毒2（SARS-CoV-2），细胞因子水平升高的患者， 通常与严重的症状和死亡率有关。这表明特定的 炎症分子可能是死亡率和发病率的一个促成因素， 病毒本身因此，迫切需要更好地了解基因激活动力学， 并开发治疗方法来控制炎症反应。2016年，我们展示了 控制炎症基因染色质重塑的表观遗传抑制因子， 拓扑异构酶1，可以减少炎症基因的表达和挽救细菌感染过程中的致命性， 和病毒感染，这表明这些效应可能适用于COVID-19的情况， 好.拓扑异构酶1抑制剂是FDA批准的，并在WHO基本药物清单中， 因此，如果它们对COVID-19有效，它们的广泛使用和廉价成本可以发挥作用 就像其他感染一样。在本提案中，我们将描述Top1的作用， 在SARS-CoV-2感染期间控制染色质拓扑结构的表观遗传因素，并将测试 在动物模型中使用Top1抑制剂作为治疗COVID-19药物的可行性。我们 将使用表观遗传抑制剂进行机制和临床前试验， 临床试验中使用的免疫阻断剂和当前的护理标准（糖皮质激素）。

PROJECT SUMMARY Infection causes inflammation, which contributes to pathogen clearance and survival of the host organism. However, failure to regulate the inflammatory response can often lead to multiple organ damage and lethality for the host. In the current COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with elevated cytokine levels are often associated with severe symptoms and mortality. This indicates hyper-activation of specific inflammatory molecules might be as much a contributing factor to mortality and morbidity as the virus itself. Thus, there is a dire need to better understand the gene activation dynamics upon infection and develop therapies to manage the inflammatory response. In 2016 we have shown that epigenetic inhibition of factors controlling chromatin remodeling of inflammatory genes, like Topoisomerase 1, can reduce inflammatory gene expression and rescue lethality during bacterial and viral infection, suggesting that these effects may be applicable in the setting of COVID-19 as well. Topoisomerase 1 inhibitors are FDA approved and in the list of WHO essential medicines, thus their widespread usage and cheap cost can be leverage if they are active against COVID-19 as they are in many other infections. In this proposal, we will characterize the role of Top1 and epigenetic factors controlling chromatin topology during SARS-CoV-2 infection and will test the feasibility of use of Top1 inhibitors as drugs for the treatment of COVID-19 in animal models. We will perform mechanistic and preclinical test using epigenetic inhibitors in comparison with immune blockers used in clinical trials and the current standard of care (glucocorticoids).