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

项目概要 2019 年 12 月，一种新型冠状病毒（SARS-CoV-2）在中国武汉市出现，并迅速传播 在世界范围内，病例和死亡人数不断增加。在未接触过这种新病原体的人群中， 感染个体之间存在巨大的个体间临床变异，范围从无症状感染到 致命的冠状病毒传染病-19 (COVID-19)，通常由肺炎引起，很少由肺炎引起 脑炎。在 20 岁以下人群中，感染与严重/危及生命的比率估计为 < 1/1,000， 20-50岁人群中大约为5/1,000，50岁以上人群中>1/100，80岁以上人群中>1/10。基础医疗 条件也大大增加了严重 COVID-19 的风险。另一方面，极少数情况下明显 对感染本身的抵抗力也已被确定（病毒 PCR 阴性和血清阴性个体 尽管反复并确认暴露）。在这种情况下，我们假设单基因先天性错误 免疫（IEI）可能是先前健康的年轻人（<50 年），而单基因先天性耐药变异（IVR）可能会保护其他个体免受 SARS-CoV- 2感染。这两种假设均基于 25 年对多种其他病毒感染的研究，其中 IEI（例如流感病毒肺炎）和IVR（例如对人类免疫缺陷病毒的抵抗力）已被 确定。我们不仅会在美国招募 IEI 和 IVR 队列，重要的是还会在国际上招募 水平；使用我们实验室开发的尖端策略搜索候选致病变异 分析全外显子组测序（WES）数据；并进行深入的功能研究来表征 对候选基因型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“特发性”新冠病毒的人类遗传和免疫学基础 19 和对 SARS-CoV-2 的天然抵抗力。我们的初步结果令人兴奋。在不到2个月的时间里，我们和 Helen Su (NIAID) 组织了全球范围内不断发展的“新冠人类基因努力”(CHGE)，超过 400 合作者和 50 个国家的 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 筛选出5个有前景的候选基因（IKFZ1、POLR3C、TLR7、IRF7、IL22），这些基因均参与抗病毒 干扰素免疫。我们的计划重点关注及时出现的问题（以前健康的年轻人感染了严重的新冠病毒） 患者和个人对感染具有天然抵抗力），测试了一个大胆但合理的假设（单基因基础） 对于两组异常值），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 允许基因诊断和咨询，同时促进新型预防和治疗方法的开发 策略包括抗病毒药物（例如旨在恢复有缺陷的免疫力或阻止病毒进入）和 在遗传和非遗传病例中接种疫苗（例如旨在增强某些免疫途径）。

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.