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 一种新型的冠状病毒，严重的急性呼吸综合征冠状病毒2（SARS-COV-2），已经很快 自2019年12月以来遍及世界各地，并在 种群天真地遵循这种新的病原体。自2020年5月初以来，这是一种罕见且威胁生命的SARS-COV-2 川崎样疾病，由CDC指定为儿童多系统炎症综合征（MIS-C）， 出现在COVID-19的率高的社区中。患者的临床和实验室特征 揭示了MIS-C和川崎病（KD）之间的多个相似之处，这是一个知名但知之甚少的 小儿炎症状况。过去〜50年的KD研究表明，感染因素，包括 尤其是多种病毒，可能会触发炎症性级联反应，以驱动临床表现 遗传脆弱的孩子。但是，KD的遗传病因和免疫学机制仍然存在 在很大程度上未知。 MIS-C在Covid-19期间的流行中的出现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。我们和其他人以前已经确定了 一单基因预防性误差（IEI）的数量，存在多种严重病毒疾病的基础。我们现在瞄准 通过检验单基因假设来剖析MIS-C的免疫发作。我们将招募一组 使用Covid人类遗传努力（www.covidhge.com），至少有1,000名MIS-C患者，我们的全球 儿科医生网络和纽约州卫生部（NYSDOH）。我们将表现完整 所有参考患者依次依次依次针对所有参与患者的外显子组测序（WES）和整个基因组测序（WGS）。我们将 通过分析该方法，通过公正的基因组方法搜索罕见的单基因IEIS IEIS。 队列人群（遗传同质性）和个体患者水平（遗传学）的WES和WGS数据 异质性），还测试了免疫同质性和异质性的模型。对于所有候选人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，以连接 与MIS-C发病机理相关的分子机制和细胞表型的候选基因型。 我们将使用患者特异性的白细胞，皮肤成纤维细胞和人类多能干细胞（HPSC）衍生的MIS- C疾病与疾病相关的细胞类型，例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，并在其中620例中进行了WES。为了进行比较， 我们还招募了158例经典KD患者，并对所有患者进行了测序。这个项目重点是 及时而毁灭性的问题，检验一个大胆但合理的假设，并利用尖端 遗传和机械方法。它将使我们能够深入了解该分子和细胞的基础 以前健康的儿童和青少年中SARS-COV-2相关的MIS-C的免疫病理学。结果 该项目还将允许遗传诊断和咨询，同时促进新颖的发展 在遗传和非遗传病例中的预防和治疗策略。