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

协作交叉中 COVID-19 易感性和耐药性决定因素的遗传分析

• 批准号: 10463708
• 负责人: Ralph S Baric
• 金额: $ 76.61万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463708
• 关键词: 2019-nCoV; Acute Respiratory Distress Syndrome; Affect; Age; Animal Model; Antiviral Agents; COVID-19; COVID-19 pathogenesis; COVID-19 pneumonia; COVID-19 susceptibility; CRISPR/Cas technology; Candidate Disease Gene; Cessation of life; Coronavirus; Custom; Development; Disease; Disease Outcome; Disease susceptibility; Exhibits; Factor Analysis; Gender; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Health; Healthcare Systems; Homeostasis; Human; Immune; Immune response; Immunity; Individual; Infection; Inflammatory; Integration Host Factors; Knowledge; Laboratories; Laboratory mice; Lung; Maps; Medical; Middle East Respiratory Syndrome Coronavirus; Modeling; Mouse Strains; Mus; Pathogenesis; Pathway interactions; Patients; Preclinical Drug Evaluation; Preclinical Testing; Predisposition; Public Health; Pulmonary Pathology; Quantitative Trait Loci; Research; Resistance; Respiratory physiology; Risk; Risk Factors; SARS coronavirus; Safety; Shapes; Statistical Models; Susceptibility Gene; Testing; Therapeutic; Vaccines; Variant; Virus; Virus Diseases; Work; base; coronavirus disease; coronavirus vaccine; disorder risk; experience; genetic analysis; genomic locus; human model; improved; influenzavirus; insight; male; men; monocyte; mouse model; nonhuman primate; novel coronavirus; novel vaccines; pandemic disease; pathogen; phenotypic data; prognostic assays; remdesivir; resistant strain; respiratory infection virus; response; sex; zoonotic coronavirus

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.

摘要： 2019年nCoV（SARS-CoV 2或nCoV 2）目前正在造成全球大流行，并有望造成数百万人死亡。 感染，数十万人死亡，并严重破坏医疗保健系统和经济 在全球nCoV 2是一种2B组冠状病毒，与严重急性呼吸系统综合征有75%相同 冠状病毒（SARS-CoV），出现于2003年。大约10%的nCoV 2感染导致COVID-19 肺炎进展为急性呼吸窘迫综合征（ARDS），而其他肺炎的很大一部分 个别人士没有病征或病情轻微。年龄性别和潜在的健康状况 使个体易患严重疾病/死亡，我们对疾病的驱动因素了解甚少 结果。这些知识对于了解COVID-19的发病机制以及 开发和测试安全有效的nCoV疫苗和疗法。然而，尽管患者研究 可以提供深入了解疾病的危险因素，这些因素的机制分析将需要强大的动物 COVID-19疾病的模型。不幸的是，nCoV不能在标准实验室小鼠中复制， 存在对复制包括ARDS的类人COVID-19疾病的新动物模型的显著需求。 协作交叉（CC）小鼠对SARS-CoV的反应差异很大，我们能够采取 这种变异的优势在于既能开发新的SARS-CoV诱导的疾病模型，同时还能识别宿主 遗传因素调节疾病的结果。根据这一经验，我们建议利用新的 小鼠适应的SARS-CoV 2病毒（maCoV 2）是Baric实验室最近开发的，用于筛选 一组CC小鼠品系对maCoV 2诱导的疾病的易感性。这项工作将完成两个关键的 研究目标：1）开发急需的nCoV 2诱导疾病的小鼠模型，以及2） 鉴定调节对nCoV 2疾病的抗性或易感性的多态性宿主基因/途径。