Monogenic basis of resistance to SARS-CoV2 and predisposition to severe COVID-19

项目摘要 2019年12月，武汉市出现新型冠状病毒(SARS-CoV-2)中国，并迅速传播 在世界范围内，病例和死亡人数不断增加。在对这种新病原体天真的人群中，有 从无症状感染到无症状感染，感染个体之间的临床差异很大 对致命性冠状病毒传染病-19(新冠肺炎)，通常是由于肺炎，很少会 脑炎。据估计，在20年内，严重感染/危及生命的比率为1/1000， 20-50岁的人约为千分之五，50岁的人约为1/100，80岁的人约为1/10。基础医疗 病情也大大增加了严重新冠肺炎的风险。另一方面，罕见的明显的 还发现了对感染本身的抵抗力(病毒聚合酶链式反应阴性和血清阴性的人 尽管反复和确认暴露)。在这种情况下，我们假设先天的单基因错误 免疫力可能是先前健康的年轻个体感染新冠肺炎并危及生命的基础(&lt；50 年)，而单基因先天抗药性变异(IVR)可能保护其他个人免受SARS-CoV- 2感染。这两种假设都是基于25年来对广泛的其他病毒感染的研究，对于这些病毒感染 IEI(如流感病毒肺炎)和IVR(如对人类免疫缺陷病毒的抵抗力)一直是 已确认身份。我们不仅将在美国招募IEI和IVR人员，更重要的是，还将在国际 水平；使用我们实验室开发的尖端策略搜索候选致病变异 分析完整外显子测序(WES)数据；并进行深入的功能研究，以表征 对候选基因的产物进行生化分析，并对相应患者的细胞进行免疫学分析。 我们的计划旨在发现严重的特发性COVID的人类遗传和免疫学基础- 19和对SARS-CoV-2的自然抵抗力。我们的初步结果令人兴奋。在不到两个月的时间里，我们和 海伦·苏(NIAID)组织了全球性的、不断增长的“COVID人类遗传努力”(CHGE)，有400多人 50个国家和地区的合作者和40个测序中心(www.covidhge.com)。上个月，我们自己的枢纽 对IEI队列中的100多名患者进行了测序，并在IVR队列中招募了2名患者。我们已经这么做了 筛选出5个与抗病毒相关的候选基因(IKFZ1、POLR3C、TLR7、IRF7、IL22) 干扰素免疫。我们的节目关注的是一个及时的问题(以前健康的年轻人患有严重的COVID 患者和个人天生对感染具有抵抗力)，检验了一个大胆但可信的假设(单基因基础 两组异常值)，并使用尖端的遗传和机制研究(包括对 白细胞亚群和诱导多能干细胞(IPSC)来源的肺上皮细胞)。我们的项目将 允许基因诊断和咨询，同时促进新的预防和治疗方法的开发 战略，包括抗病毒药物(例如，旨在恢复免疫缺陷或阻止病毒入侵)和 在遗传和非遗传病例中接种疫苗(例如，旨在促进某些免疫途径)。

Project Summary In December 2019, a novel coronavirus (SARS-CoV-2) emerged in the city of Wuhan, China, and quickly spread worldwide, with an increasing number of cases and deaths. In populations naive to this new pathogen, there has been immense inter-individual clinical variability among infected individuals, ranging from asymptomatic infection to lethal coronavirus infectious disease-19 (COVID-19), which is typically due to pneumonitis and rarely to encephalitis. The infection to severe/life-threatening ratio is estimated to be < 1/1,000 in people <20 years, around 5/1,000 in people 20-50 years, >1/100 over 50 years, and > 1/10 over 80 years. Underlying medical conditions also greatly increase the risk of severe COVID-19. On the other hand, rare cases of apparent resistance to the infection itself have also been identified (viral PCR-negative and seronegative individuals despite repeated and confirmed exposure). In this context, we hypothesize that monogenic inborn errors of immunity (IEI) may underlie life-threatening COVID-19 infections in previously healthy, young individuals (<50 years), whereas monogenic inborn variations of resistance (IVR) may protect other individuals from SARS-CoV- 2 infection. Both hypotheses are based on 25 years of studies of a wide range of other viral infections, for which IEI (e.g. influenza virus pneumonitis) and IVR (e.g. resistance to human immunodeficiency virus) have been identified. We will recruit both IEI and IVR cohorts not only in the USA but also, importantly, at the international level; search for candidate disease-causing variants using a cutting-edge strategy developed in our laboratory to analyze whole-exome sequencing (WES) data; and perform in-depth functional studies to characterize the products of candidate genotypes biochemically, and to analyze the corresponding patients’ cells immunologically. Our program aims to discover the human genetic and immunological basis of both severe “idiopathic” COVID- 19 and natural resistance to SARS-CoV-2. Our preliminary results are exciting. In less than 2 months, we and Helen Su (NIAID) have organized the global and growing “COVID Human Genetic Effort” (CHGE), with over 400 collaborators and 40 sequencing hubs in 50 countries (www.covidhge.com). In the last month, our own hub sequenced over 100 patients in the IEI cohort and enrolled 2 individuals in the IVR cohort. We have already selected 5 promising candidate genes (IKFZ1, POLR3C,TLR7, IRF7, IL22), which are all involved in anti-viral interferon immunity. Our program focuses on a timely problem (severe COVID in previously healthy young patients and individuals naturally resistant to infection), tests a bold but plausible hypothesis (monogenic basis for both groups of outliers), and uses cutting-edge genetic and mechanistic studies (including the study of leukocyte subsets and induced pluripotent stem cells (iPSC)-derived pulmonary epithelial cells). Our project will permit genetic diagnosis and counseling, while facilitating the development of novel preventive and therapeutic strategies including anti-viral drugs (e.g. aimed at restoring a deficient immunity or blocking viral entry) and vaccines (e.g. aimed at boosting certain immunological pathways) in both genetic and non-genetic cases.