Systems Immunogenetics of Emerging Coronavirus Infections in the Collaborative Cross

SARS-CoV-2正在引发一场史无前例的大流行，可能导致数百万人死亡，具有毁灭性的 经济和公共卫生后果。约10%的SARS-CoV-2感染导致新冠肺炎 发展为急性呼吸窘迫综合征(ARDS)的肺炎。越来越多的证据 表明宿主炎症反应在推动严重疾病结局方面发挥着重要作用。因此， 了解SARS-CoV-2是如何与宿主炎症反应相互作用从而驱动新冠肺炎是至关重要的 发病机制。最近的研究表明，蝙蝠是2b组冠状病毒的天然储备者，如 SARS-CoV-2，已经抑制了NLRP3的功能，这可能允许这些病毒感染蝙蝠而不会导致 严重的疾病。这表明NLRP3或其他NLR炎性小体可能在SARS-CoV-2诱导的炎症中发挥重要作用，从而推动病毒诱导的呼吸道病理。考虑到这些基因和 在人类中，通路也是多态的，这增加了NLR基因网络中的遗传变异的可能性 可能与SARS-CoV-2易感性的变化有关。因此，我们建议利用我们的 研究团队在SARS-CoV-2致病机理和小鼠遗传学方面的独特能力直接测试 NLRP3或其他NLR炎症体通路参与SARS-CoV2诱导的疾病。我们还将测试 这些途径中的基因变异是否会影响疾病结果或病毒诱导的免疫。这一努力将 通过与Gary Nolan博士和Richard Ulevitch博士(U19AI100627)的合作进一步加强，这将 允许我们测试这些基因/途径在人类感染SARS-CoV-2期间是否被激活。因此， 建议的研究属于U19AI100625的范围或父母资助，实现了三项批判性研究 目的：1)检测NLRP3及其相关通路在SARS-CoV-2致病机制中的作用；2) 测试这些途径中的基因变异是否会影响SARS-CoV-2诱导的炎症反应或 获得性免疫，以及3)开发复制新冠肺炎病关键特征的新型小鼠模型 发病机制和炎症。

SARS-CoV-2 is causing an unprecedented pandemic that is likely to result in millions of deaths, with devastating economic and public health consequences. Approximately 10% of SARS-CoV-2 infections result in COVID-19 pneumonia that progresses to acute respiratory distress syndrome (ARDS). A growing body of evidence suggests that the host inflammatory response plays a major role in driving severe disease outcomes. Therefore, it is essential to understand how SARS-CoV-2 interacts with the host inflammatory response to drive COVID-19 pathogenesis. Recent studies suggest that bats, which are the natural reservoir of group 2b coronaviruses like SARS-CoV-2, have dampened NLRP3 function, which may allow these viruses to infect bats without causing serious disease. This indicates that NLRP3 or other NLR inflammasomes, may play an important role in SARS-CoV-2-induced inflammation and thereby drive virus-induced respiratory pathology. Given that these genes and pathways are also polymorphic in humans, this raises the possibility that genetic variation in NLR gene networks may contribute to variation in SARS-CoV-2 susceptibility. Therefore, we propose to take advantage of our research team’s unique capabilities in SARS-CoV-2 pathogenesis and mouse genetics to directly test whether NLRP3 or other NLR inflammasome pathways contribute to SARS-CoV2-induced disease. We will also test whether genetic variation in these pathways affects disease outcome or virus-induced immunity. This effort will be further enhanced by a collaboration with Drs. Gary Nolan and Richard Ulevitch (U19AI100627), which will allow us to test whether these genes/pathways are activated during SARS-CoV-2 infection in humans. Therefore, the proposed studies, which fall within the scope or the parent grant U19AI100625, achieve three critical research goals by: 1) testing the role of NLRP3 and related pathways in driving SARS-CoV-2 disease pathogenesis, 2) testing whether genetic variation in these pathways affects SARS-CoV-2-induced inflammatory responses or adaptive immunity, and 3) developing novel mouse models that reproduce key features of COVID-19 disease pathogenesis and inflammation.