Inherited IRF9 deficiency: a novel genetic etiology of severe influenza

遗传性 IRF9 缺陷：严重流感的新遗传病因

基本信息

批准号：
9510816
负责人：
Jean-Laurent Casanova
金额：
$ 25.43万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-09 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9510816
关键词：
Adult Adverse reactions Affect Alleles Animals Antiviral Agents Asthma Automobile Driving Bacterial Infections Bacterial Pneumonia Biochemical Biological Cardiovascular Diseases Cells Cessation of life Child Childhood Chronic lung disease Clinical Collection Communicable Diseases Comorbidity Complex Data Defect Dendritic Cells Disease Environment Epidemic Epithelial Cells Etiology Family Genes Genetic Genetic Drift Genetic Predisposition to Disease Genetic Transcription Genome Health Hereditary Disease Heritability Hospitalization Human IFNAR1 gene IFNAR2 gene Immunity Immunologics Impairment Individual Infection Influenza Influenza A virus Inherited Interferon-alpha Interferons Investigation Laboratories Life Lung Lung diseases Minority Molecular Mutate Mutation Mycoses Nucleotides Parents Pathogenesis Pathway interactions Patients Penetrance Phenotype Pneumonia Predisposition Privatization Production Proteins RNA RNA Splicing Recording of previous events Reporting Risk Factors Role STAT1 gene STAT2 gene Scientist Signal Transduction Site Suggestion Testing Time Vaccination Viral Genome Virus Virus Diseases Weight Zoonoses acquired immunodeficiency antiviral immunity cell type cohort congenital immunodeficiency cost design exome exome sequencing genome-wide human error improved induced pluripotent stem cell influenzavirus innovation kindred mutant novel pandemic disease pathogen programs receptor response seasonal influenza theories transcription factor transcriptome young adult

项目摘要

Project Summary Influenza A virus (IAV) is a zoonotic pathogen that causes seasonal epidemics annually and has the potential to cause worldwide pandemics. Life-threatening pneumonia occurs in only a small minority of infected individuals (0.04-0.4% of cases). Pre-existing pulmonary disease and acquired immunodeficiencies are well- known risk factors. The vast majority of severe influenza cases, however, remain unexplained, especially in children. Intriguingly, classical primary immunodeficiencies do not predispose to severe influenza. We recently reported an otherwise healthy child with severe influenza due to inherited autosomal recessive (AR) IRF7 deficiency resulting in impaired interferon (IFN)-α/β production in both plasmacytoid dendritic cells (pDCs) and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells (PECs). This was the first demonstration that influenza susceptibility could be heritable. We hypothesize that additional cases of severe influenza in children and young adults may result from single-gene inborn errors of immunity, not necessarily displaying complete penetrance. We recently performed whole-exome sequencing (WES) in a cohort of 25 patients and their parents (trio design) with life-threatening influenza without secondary bacterial pneumonia. We discovered a homozygous IRF9 mutation in a child with life-threatening influenza and a history of adverse reaction to MMR vaccination. IRF9, with STAT1 and STAT2, is one of the three subunits of ISGF3, the main transcriptional complex that drives antiviral type I IFN responses. The mutation is private to this kindred and affects an essential nucleotide at a splice site. We intend to test whether the mutation is deleterious, in terms of expression and function. We will also test the patient's cells for response to type I IFN and their control of influenza virus in the presence of type I IFNs. Finally, we will compare the genome-wide transcriptome responses to type I IFNs in the patient's cells with those from other patients with autosomal recessive, complete defects in IFNAR1, IFNAR2, STAT1, and STAT2. Our preliminary data are convincing and strong, as we showed that the splice mutation is not leaky and the encoded protein is loss of ISGF3 expression and function. Moreover, the patient's cells seem to control influenza virus poorly even in the presence of exogenous type I IFNs. Finally, we have collected cells from patients with all types of inborn errors of the type I IFN responsive pathway. Our project is thus highly innovative, yet supported by strong preliminary evidence. Collectively, our project will characterize, in depth, the molecular and cellular basis of a new primary immunodeficiency, autosomal recessive IRF9 deficiency, thereby documenting a second genetic and immunological etiology of severe influenza of childhood. This study will give weight to the emerging notion that severe influenza of childhood can be caused by single-gene inborn errors of immunity. Our study will also have new and important biological implications, providing the first analysis of IRF9-dependent and -independent responses to type I IFNs in humans. Overall, our discovery will have both biological and clinical implications.

项目摘要流感病毒（IAV）是一种死亡的病原体，导致季节性发作，并且具有潜力引起全球大流行。威胁生命的肺炎仅发生在少数被感染个人（案例为0.04-0.4％）。先前存在的肺部疾病和获得的免疫缺陷是良好的已知风险因素。但是，绝大多数严重的影响力案件仍然未知，尤其是孩子们。有趣的是，经典的原发性免疫缺陷不容易受到严重影响。我们最近报道了一个因遗传常染色体隐性（AR）IRF7而具有严重影响的健康儿童缺乏缺乏，导致干扰素（IFN） - α/β在两个浆细胞类动物树突状细胞（PDC）和诱导多能干细胞（IPSC）衍生的肺上皮细胞（PEC）。这是第一个证明影响力可能是可遗传的。我们假设其他严重案件儿童和年轻人的流感可能是由单基因天生的免疫错误造成的，没有必要显示完整的外观。最近，我们在25的队列中进行了全外观测序（WES）患者及其父母（三重奏设计）具有威胁生命的影响，没有继发性细菌性肺炎。我们在具有威胁生命的影响力和逆境史的孩子中发现了一个纯合的IRF9突变对MMR疫苗接种的反应。 IRF9与STAT1和STAT2是ISGF3的三个亚基之一，是主要的转录复合物驱动I型IFN反应的抗病毒。该突变是这种属性的私人在剪接部位影响必需的核苷酸。我们打算以表达和功能。我们还将测试患者的细胞以响应I型IFN及其对其控制 I型IFN存在的流感病毒。最后，我们将比较全基因组的转录组对患者细胞中I型IFN的反应与其他常染色体隐性患者的患者的反应， IFNAR1，IFNAR2，STAT1和STAT2的完全缺陷。我们的初步数据令人信服和强大，我们表明，剪接突变不是泄漏，编码的蛋白质是ISGF3表达的丧失，并且功能。此外，即使存在，患者的细胞似乎也很差外源I型IFN。最后，我们从具有I型的所有类型的原子误差的患者中收集了细胞 IFN响应途径。因此，我们的项目具有很高的创新性，但得到了强有力的初步证据的支持。总的来说，我们的项目将深入表征新主要的分子和细胞基础免疫缺陷，常染色体隐性IRF9缺乏症，从而记录第二个遗传和童年严重影响的免疫学病因。这项研究将使新兴通知的重量童年的严重影响可能是由单基因的免疫力造成的。我们的研究也将有新的和重要的生物学含义，提供对IRF9依赖和独立的首次分析对人类I型IFN的响应。总体而言，我们的发现将具有生物学和临床意义。