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: 10453277
• 负责人: Shen-Ying Zhang
• 金额: $ 25.43万
• 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/10453277
• 关键词: 2019-nCoV; Accounting; Adolescent; Affect; Attenuated; BIRC4 gene; Brain Stem; COVID-19; COVID-19 pandemic; COVID-19 pneumonia; Cardiac Myocytes; Cells; Centers for Disease Control and Prevention (U.S.); 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; Herpesvirus 1; 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; Population Genetics; Predisposition; Preventive; Prosencephalon; Pulmonary Inflammation; Recurrent respiratory papillomatosis; Reporting; Rhinovirus; SH2D1A gene; STAT2 gene; Sequence Analysis; Single-Gene Defect; TBK1 gene; TLR3 gene; TNF receptor-associated factor 3; Testing; Therapeutic; Therapeutic Intervention; Time; Variant; Viral; Viral Encephalitis; Virus; Virus Diseases; Yellow Fever Vaccine; 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; 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 一种新型冠状病毒，严重急性呼吸综合征冠状病毒2（SARS-CoV-2），已迅速被 自2019年12月以来在世界各地传播，并在2019年引起冠状病毒病（COVID-19）， 对这种新病原体不敏感的人群自2020年5月初以来，一种罕见的危及生命的SARS-CoV-2相关 川崎病样疾病，由CDC指定为儿童多系统炎症综合征（MIS-C）， 出现在COVID-19高发社区。患者的临床和实验室特征 揭示了MIS-C和川崎病（KD）之间的多种相似性，川崎病是一种众所周知但知之甚少的疾病， 小儿炎症。近50年来对KD的研究表明，感染因子，包括 特别是各种病毒，可以引发炎症级联反应，导致临床表现， 基因脆弱的孩子然而，KD的遗传病因学和免疫学机制仍然存在， 大部分未知。在COVID-19疫情期间出现的MIS-C提供了令人信服的证据，表明 病毒触发，至少对于这种特殊形式的川崎病。我们和其他人之前已经确定了一个 许多单基因先天性免疫缺陷（IEI）是各种严重病毒性疾病的基础。我们现在的目标是 通过检验单基因假说来剖析MIS-C的免疫发病机制。我们将招募一批 通过利用我们的全球COVID人类遗传努力（www.covidhge.com）， 儿科医生网络和纽约州卫生部（NYSDOH）。我们将执行整个 外显子组测序（WES）和全基因组测序（WGS）。我们将 通过无偏的全基因组方法，通过分析MIS-C的 队列人群（遗传同质性）和个体患者水平（遗传异质性）的WES和WGS数据 异质性），也测试免疫学同质性和异质性的模型。对于所有候选MIS-C- 引起基因，我们将在分子和细胞水平上进行深入的表征， 候选基因型与MIS-C发病机制相关的分子机制和细胞表型。 我们将使用患者特异性白细胞、真皮成纤维细胞和人多能干细胞（hPSC）衍生的MIS-1。 C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 令人鼓舞的是，我们已经招募了812名患者，并对其中620人进行了WES。作为比较， 我们还招募了158名经典KD患者，并对所有患者进行了测序。该项目的重点是一个 及时和毁灭性的问题，测试一个大胆的，但似是而非的假设，并利用尖端的 遗传学和机械学方法。它将使我们能够深入了解分子和细胞的基础， SARS-CoV-2相关MIS-C在先前健康儿童和青少年中的免疫病理学的结果 该项目还将允许遗传诊断和咨询，同时促进新的 遗传和非遗传病例的预防和治疗策略。