Genetic Analysis of COVID-19 Susceptibility and Resistance Determinants in the Collaborative Cross

摘要： 2019年新冠状病毒(SARS-CoV2或nCoV2)目前正在引发全球大流行，并有望导致数百万人 感染，数十万人死亡，并严重扰乱医疗保健系统和经济 全球范围内。NCoV2是一种2B组冠状病毒，与严重急性呼吸综合征有75%的同源性 冠状病毒(SARS-CoV)，于2003年出现。约10%的nCoV2感染导致新冠肺炎 肺炎进展为急性呼吸窘迫综合征(ARDS)，而其他相当一部分 个体无症状或发展为轻度疾病。虽然年龄、性别和潜在的健康状况 使人容易患上严重疾病/死亡，我们对导致疾病的因素了解很少。 结果。这一知识对于理解新冠肺炎的发病机制以及 开发和测试安全有效的新冠状病毒疫苗和疗法。然而，虽然患者研究 可以为疾病风险因素提供洞察力，对这些因素进行机理分析将需要健壮的动物 新冠肺炎病模型。不幸的是，nCoV不能在标准的实验室小鼠身上复制，而且 迫切需要新的动物模型来复制类似人类的新冠肺炎疾病，包括急性呼吸窘迫综合征。 协作交叉(CC)小鼠对SARS-CoV的反应差异很大，我们能够 这种变异的优势既可以开发新的SARS-CoV诱导的疾病模型，同时也可以识别宿主 调节疾病结果的遗传因素。基于这一经验，我们建议利用一种新的 小鼠适应的SARS-CoV2病毒(MaCoV2)是巴里克实验室最新开发的病毒，用于筛选 CC小鼠品系对maCoV2诱导的疾病易感性的小组。这项工作将完成两个关键的 研究目标：1)建立急需的nCoV2诱导的小鼠疾病模型；2) 确定调节对nCoV2病的抗性或易感性的多态寄主基因/途径。

Abstract: The 2019 nCoV (SARS-CoV2 or nCoV2) is currently causing a global pandemic, and is on track to cause millions of infections, hundreds of thousands of deaths, and significantly disrupt healthcare systems and economies globally. nCoV2 is a group 2B coronavirus that is 75% identical to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), which emerged in 2003. Approximately 10% of nCoV2 infections result in COVID-19 pneumonia that progresses to acute respiratory distress syndrome (ARDS), while a significant fraction of other individuals are asymptomatic or develop mild disease. While age, gender, and underlying health conditions predispose individuals to severe disease/death, we have a poor understanding of the factors that drive disease outcome. This knowledge is essential for understanding the pathogenesis of COVID-19, and for developing and testing safe and effective nCoV vaccines and therapies. However, while patient studies can provide insights into the disease risk factors, mechanistic analysis of these factors will require robust animal models of COVID-19 disease. Unfortunately, nCoV does not replicate in standard laboratory mice, and a significant need exists for new animal models that reproduce human-like COVID-19 disease, including ARDS. Collaborative Cross (CC) mice vary significantly in their response to SARS-CoV, and we were able to take advantage of this variation both to develop new models SARS-CoV-induced disease, while also identifying host genetic factors that regulate disease outcome. Based on this experience, we propose take advantage of a new mouse adapted SARS-CoV2 virus (maCoV2), which was recently developed in the Baric laboratory, to screen a panel of CC mouse strains for susceptibility to maCoV2-induced disease. This work will accomplish two critical research objectives by: 1) developing critically needed mouse models of nCoV2-induced disease, and 2) identifying polymorphic host genes/pathways that regulate resistance or susceptibility to nCoV2-disease.