Single gene inborn errors of immunity underlying SARS-CoV-2-related multisystem inflammatory syndrome in children: a new approach to tackle a seemingly old puzzle

儿童 SARS-CoV-2 相关多系统炎症综合征背后的单基因先天性免疫错误：解决看似古老难题的新方法

• 批准号: 10625476
• 负责人: Shen-Ying Zhang
• 金额: $ 21.19万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625476
• 关键词: 2019-nCoV; Accounting; Adolescent; Affect; Attenuated; BIRC4 gene; Brain Stem; COVID-19; COVID-19 pandemic; COVID-19 pneumonia; Cardiac Myocytes; Cells; Characteristics; Child; Childhood; Clinical; Collaborations; Communities; Cytomegalovirus; Data; Defect; Dermal; Development; Disease; Encephalitis; Endothelial Cells; Enrollment; Epidermodysplasia Verruciformis; Family member; Fibroblasts; Gene Frequency; Genes; Genetic; Genetic Counseling; Genetic Heterogeneity; Genetic Models; Genetic Predisposition to Disease; Genotype; Health; Hepatitis; Hepatitis A Virus; Hereditary Disease; Herpes encephalitis; Herpesvirus Type 3; Heterogeneity; Human; Human Genetics; Human Herpesvirus 4; Human Papillomavirus; IFNAR1 gene; IFNAR2 gene; IRF3 gene; Immunity; Immunological Models; Immunologics; Impairment; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Influenza A virus; Intervention; Investigation; Laboratories; Leukocytes; Life; Measles; Minor; Molecular; Mucocutaneous Lymph Node Syndrome; Multisystem Inflammatory Syndrome in Children; Mutate; Mutation; NOS2A gene; New York; Pathogenesis; Patient Recruitments; Patients; Phenotype; Population; Predisposition; Preventive; Prosencephalon; Pulmonary Inflammation; Recurrent respiratory papillomatosis; Reporting; Rhinovirus; SH2D1A gene; STAT2 gene; Single-Gene Defect; TBK1 gene; TLR3 gene; TNF receptor-associated factor 3; Testing; Therapeutic; Therapeutic Intervention; Variant; Viral; Viral Encephalitis; Virus; Virus Diseases; Yellow Fever Vaccine; autosome; cardiovascular endothelium; cell type; cohort; coronavirus disease; design; emerging pathogen; exome; exome sequencing; gene product; genetic disorder diagnosis; genome sequencing; genome-wide; human pluripotent stem cell; immunopathology; individual patient; innovation; insight; non-genetic; novel; novel coronavirus; novel strategies; participant enrollment; pediatric patients; pediatrician; preventive intervention; proband; recruit; severe COVID-19; whole genome; young adult

Project Summary A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been quickly spreading around the world since December 2019 and causing coronavirus disease 2019 (COVID-19) in populations naive to this new pathogen. Since early May 2020, a rare and life-threatening SARS-CoV-2-related Kawasaki-like disease, designated by the CDC as Multisystem Inflammatory Syndrome in Children (MIS-C), emerged in communities with high rates of COVID-19. Clinical and laboratory characteristics of patients have revealed multiple similarities between MIS-C and Kawasaki disease (KD), a well-known but poorly understood pediatric inflammatory condition. The past ~50 years of studies on KD suggest that infectious agents, including a variety of viruses in particular, can trigger an inflammatory cascade that drives the clinical manifestations in genetically vulnerable children. However, the genetic etiologies and immunological mechanisms of KD remain largely unknown. The emergence of MIS-C during the COVID-19 epidemic provides compelling evidence of a viral trigger, at least for this specific form of Kawasaki-like disease. We and others have previously identified a number of monogenic inborn errors of immunity (IEIs) underlying a variety of severe viral diseases. We now aim to dissect the immunopathogenesis of MIS-C by testing a monogenic hypothesis. We will recruit a cohort of at least 1,000 MIS-C patients, by utilizing the COVID Human Genetic Effort (www.covidhge.com), our global network of pediatricians, and the New York State Department of Health (NYSDOH). We will perform whole exome sequencing (WES) and whole genome sequencing (WGS) sequentially for all enrolled patients. We will search for rare single gene IEIs underlying MIS-C via an unbiased genome-wide approach, by analyzing the WES and WGS data at the cohort population (genetic homogeneity) and individual patient levels (genetic heterogeneity), also testing models of immunological homogeneity and heterogeneity. For all candidate MIS-C- causing genes, we will perform in-depth characterization at the molecular and cellular levels, to connect the candidate genotype to molecular mechanism(s) and cellular phenotype(s) relevant to the MIS-C pathogenesis. We will use patient-specific leukocytes, dermal fibroblasts, and human pluripotent stem cell (hPSC)-derived MIS- C disease-relevant cell types, such as cardiovascular endothelial cells or cardiomyocytes. Our preliminary data are encouraging, as we have already enrolled 812 patients and performed WES on 620 of them. For comparison, we have also enrolled 158 patients with classic KD and have sequenced all of them. This project focuses on a timely and devastating problem, tests a bold but plausible hypothesis, and takes advantage of cutting-edge genetic and mechanistic approaches. It will enable us to gain insight into the molecular and cellular basis of the immunopathology of SARS-CoV-2-related MIS-C in previously healthy children and adolescents. The results of this project will also permit genetic diagnosis and counseling, while facilitating the development of novel preventive and therapeutic strategies in both genetic and non-genetic cases.

项目摘要 一种新的冠状病毒--严重急性呼吸综合征冠状病毒2(SARS-CoV-2) 2019年12月起全球传播并引发2019年冠状病毒病(新冠肺炎) 人们对这种新的病原体很天真。自2020年5月初以来，一种罕见的危及生命的SARS-CoV-2相关病毒 川崎病，被疾控中心指定为儿童多系统炎症综合征(MIS-C)， 出现在新冠肺炎使用率较高的社区。患者的临床和实验室特征有 揭示了MIS-C和川崎病(KD)之间的许多相似之处，川崎病是一种众所周知但知之甚少的疾病 儿科炎症状况。过去50年对KD的研究表明，感染性病原体，包括 尤其是各种病毒，可以触发炎症级联反应，从而推动临床表现 遗传脆弱的儿童。然而，KD的遗传病因和免疫学机制仍然存在。 很大程度上是未知的。新冠肺炎疫情期间出现的管理信息系统-C提供了令人信服的证据 病毒触发，至少对于这种特定形式的川崎样疾病是如此。我们和其他人之前已经确定了一个 各种严重病毒性疾病潜在的单基因先天性免疫错误(IEIS)的数量。我们现在的目标是 通过检验一种单基因假说来剖析MISC的免疫发病机制。我们将招募一批AT 通过利用COVID人类遗传努力(www.covidhge.com)，至少1000名MIS-C患者，我们的全球 儿科医生网络和纽约州卫生局(Nysdoh)。我们将完整地表演 对所有入选患者进行外显子组测序(WES)和全基因组测序(WGS)。我们会 通过一种无偏见的全基因组方法，通过分析 队列人群(遗传同质性)和个体患者水平(遗传同质性)的WES和WGS数据 异质性)，还测试免疫同质性和异质性的模型。对于所有候选的管理信息系统-C- 导致基因，我们将在分子和细胞层面进行深入的表征，以连接 与MISC发病相关的候选基因的分子机制(S)和细胞表型(S)。 我们将使用患者特有的白细胞、真皮成纤维细胞和人类多能干细胞(HPSC)来源的MIS. 与疾病相关的细胞类型，如心血管内皮细胞或心肌细胞。我们的初步数据 令人鼓舞，因为我们已经招募了812名患者，并对其中620名患者进行了WES。作为比较， 我们还招募了158名患有经典KD的患者，并对他们进行了测序。本项目的重点是 及时而具破坏性的问题，检验大胆但可信的假设，并利用尖端技术 遗传和机械方法。这将使我们能够深入了解人类免疫缺陷的分子和细胞基础 既往健康儿童和青少年SARS-CoV-2相关MIS-C的免疫病理学研究结果是 该项目还将允许进行基因诊断和咨询，同时促进新技术的开发 遗传性和非遗传性病例的预防和治疗策略。