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

项目摘要 2019年12月，一种新型冠状病毒（SARS-CoV-2）在中国武汉市出现，并迅速蔓延 在世界范围内，病例和死亡人数不断增加。在对这种新病原体不敏感的人群中， 在感染个体中存在巨大的个体间临床变异性， 致命的冠状病毒传染病-19（COVID-19），通常是由于肺炎，很少 脑炎在<20岁的人群中，感染与严重/危及生命的比率估计为< 1/1，000， 20-50岁人群中约为5/1，000，50岁以上>1/100，80岁以上> 1/10。潜在的医疗 条件也大大增加了严重COVID-19的风险。另一方面，罕见的明显 对感染本身的抗性也已被鉴定（病毒PCR阴性和血清阴性个体 尽管有反复和确认的暴露）。在这种情况下，我们假设单基因先天性错误， 免疫力（IEI）可能是先前健康的年轻个体（<50 年），而单基因先天抗性变异（IVR）可能保护其他个体免受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， IEI（例如流感病毒性肺炎）和IVR（例如对人类免疫缺陷病毒的耐药性）已被 鉴定我们将招募IEI和IVR队列不仅在美国，而且，重要的是，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体 分析全外显子组测序（WES）数据;并进行深入的功能研究，以表征 候选基因型的产物，并对相应患者的细胞进行免疫学分析。 我们的项目旨在发现严重的“特发性”COVID-19的人类遗传和免疫学基础。 19和对SARS-CoV-2的天然抗性。我们的初步结果令人兴奋。不到两个月，我们和 Helen Su（NIAID）组织了全球范围内不断发展的“COVID人类遗传努力”（CHGE）， 在50个国家有40个测序中心（www.covidhge.com）。上个月，我们自己的中心 对IEI队列中的100多名患者进行测序，并在IVR队列中招募2名个体。我们已经 筛选出5个有希望的候选基因（IKFZ 1、POLR 3C、TLR 7、IRF 7、IL 22），它们都与抗病毒相关， 干扰素免疫我们的计划侧重于一个及时的问题（严重的COVID在以前健康的年轻人 患者和自然抵抗感染的个体），检验了一个大胆但似乎合理的假设（单基因基础 对于这两组离群值），并使用尖端的遗传和机制研究（包括研究 白细胞亚群和诱导多能干细胞（iPSC）衍生的肺上皮细胞）。我们的项目将 允许遗传诊断和咨询，同时促进新的预防和治疗方法的发展， 策略包括抗病毒药物（例如，旨在恢复免疫缺陷或阻断病毒进入），以及 在遗传和非遗传情况下的疫苗（例如，旨在加强某些免疫途径）。

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.