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

抗 SARS-CoV2 的单基因基础和严重 COVID-19 的易感性

• 批准号: 10265642
• 负责人: Jean-Laurent Casanova
• 金额: $ 44.6万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-06 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265642
• 关键词: Acyclovir; Affect; Alleles; Architecture; Biochemical; Brain Stem; Candidate Disease Gene; Cells; Child; Childhood; Clinical; Collection; Communicable Diseases; Complication; Country; Data; Disease; Encephalitis; Enrollment; Family; Fibroblasts; Funding; Genes; Genetic; Genetic Counseling; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic study; Genotype; Hereditary Disease; Herpes encephalitis; Herpesvirus 1; Heterogeneity; Human Genetics; IFNAR1 gene; IRF3 gene; Immunity; Immunologics; Impairment; Individual; Infection; Interferon-alpha; Interferons; International; Laboratories; Lesion; Leukocytes; Life; Mediating; Mendelian disorder; Minority; Modeling; Molecular; Molecular Diagnosis; Molecular Genetics; Mutation; Neuraxis; Neurologic; Neurons; Olfactory Nerve; Organ; Parents; Pathogenesis; Pathway interactions; Patients; Penetrance; Phenotype; Physiological; Population; Primary Infection; Privatization; Prosencephalon; RIPK1 gene; RIPK3 gene; Research; Resistance; Solid; Survivors; TBK1 gene; TLR3 gene; TNF receptor-associated factor 3; Techniques; Testing; Trigeminal nerve structure; United States National Institutes of Health; Validation; Variant; Viral Encephalitis; Work; base; candidate selection; clinical care; cohort; congenital immunodeficiency; design; exome sequencing; genetic analysis; genetic linkage analysis; genome sequencing; genome-wide; genome-wide linkage; induced pluripotent stem cell; innovation; kindred; mutant; next generation sequencing; novel; novel therapeutic intervention; recruit; response; trait; transcriptome sequencing; whole genome

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.

项目摘要 2019年12月，中国武汉市出现了一个新颖的冠状病毒（SARS-COV-2），并迅速传播 全球，案件和死亡人数越来越多。在这种新病原体天真的人群中，有 是受感染个体之间的巨大个体间临床变异性，从无症状感染范围 致命性冠状病毒感染性疾病19（COVID-19），通常是由于肺炎引起的，很少是由于 脑炎。严重/威胁生命比率的感染估计<1/1,000 <20年， 大约5/1,000人20至50年，在50年内> 1/100> 1/100，在80年中> 1/10。基础医疗 条件也大大增加了严重的共同19岁的风险。另一方面，罕见的外观案例 还已经鉴定出对感染本身的抗性（病毒PCR阴性和血清神经个体 尽管重复并确认暴露）。在这种情况下，我们假设是单基因的原本错误 免疫力（IEI）可能是先前健康的年轻人（<50）的威胁生命的19009感染的基础（<50 几年），而耐药性（IVR）的单基因天生变化可能会保护其他个体免受SARS-COV- 2感染。这两个假设均基于对广泛的其他病毒感染的25年研究，为此 IEI（例如影响力病毒肺炎）和IVR（例如对人免疫缺陷病毒的抗性）已是 确定。我们将不仅在美国招募IEI和IVR队列 等级;使用实验室中制定的尖端策略搜索引起候选病的变体 分析全外观测序（WES）数据；并进行深入的功能研究以表征 候选基因型的产物生化，并通过免疫学分析相应的患者细胞。 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2个月的时间里，我们和 海伦·苏（Helen Su）（Niaid）组织了全球和不断增长的“共同遗传努力”（CHGE），超过400 在50个国家 /地区的合作者和40个测序中心（www.covidhge.com）。在上个月，我们自己的枢纽 在IEI队列中测序了100多名患者，并在IVR队列中招募了2个个体。我们已经 选定的5个有前途的候选基因（IKFZ1，Polr3C，TLR7，IRF7，IL22），它们都参与抗病毒 干扰素免疫。我们的计划着重于及时的问题（以前健康的年轻人严重的互联 患者和个体自然抗感染具有抗性），测试了一个大胆但合理的假设（单基础） 对于两组异常值），并使用尖端的遗传和机械研究（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，同时支持新型预防和治疗的发展 包括抗病毒药物在内的策略（例如，旨在恢复不足的免疫力或阻止病毒入口）和 在遗传和非遗传病例中，疫苗（例如，旨在提高某些免疫途径）。