Systems Immunogenetics of Emerging Coronavirus Infections in the Collaborative Cross

SARS-CoV-2正在引起一场前所未有的大流行，可能导致数百万人死亡， 经济和公共卫生后果。大约10%的SARS-CoV-2感染导致COVID-19 肺炎进展为急性呼吸窘迫综合征（ARDS）。越来越多的证据 表明宿主炎症反应在驱动严重疾病结果中起主要作用。因此，我们认为， 了解SARS-CoV-2如何与宿主炎症反应相互作用以驱动COVID-19是至关重要的 发病机制最近的研究表明，蝙蝠是2b组冠状病毒的天然宿主，例如 SARS-CoV-2抑制了NLRP 3的功能，这可能使这些病毒感染蝙蝠而不会引起 严重的疾病。这表明NLRP 3或其他NLR炎性体可能在SARS-CoV-2诱导的炎症中发挥重要作用，从而驱动病毒诱导的呼吸道病理学。鉴于这些基因和 通路在人类中也是多态的，这增加了NLR基因网络中遗传变异的可能性。 可能导致SARS-CoV-2易感性的变化。因此，我们建议利用 研究小组在SARS-CoV-2发病机制和小鼠遗传学方面的独特能力， NLRP 3或其他NLR炎性体通路有助于SARS-CoV 2诱导的疾病。我们还将测试 这些途径中的遗传变异是否影响疾病结果或病毒诱导的免疫力。这一努力将 通过与加里诺兰和理查德Ulevitch博士（U19 AI 100627）的合作，将进一步加强， 让我们测试这些基因/通路是否在人类感染SARS-CoV-2期间被激活。因此，我们认为， 这些建议的研究属于U19 AI 100625的范围，它们完成了三项关键性的研究 目标是：1）测试NLRP 3和相关通路在驱动SARS-CoV-2疾病发病机制中的作用，2） 测试这些途径中的遗传变异是否影响SARS-CoV-2诱导的炎症反应， 获得性免疫，以及3）开发新的小鼠模型，重现COVID-19疾病的关键特征 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.