IFN responses and SARS-CoV-2 Receptor ACE2 Expression in the airway epithelium of young children with Down Syndrome

唐氏综合症幼儿气道上皮中的 IFN 反应和 SARS-CoV-2 受体 ACE2 表达

• 批准号: 10215714
• 负责人: JYOTI K JAISWAL
• 金额: $ 48.97万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215714
• 关键词: 2019-nCoV; Address; Adult; Antiviral Agents; Antiviral Response; Applications Grants; Area; Binding Sites; Biological Assay; COVID-19; COVID-19 pandemic; Caring; Cells; Child; Chromosome 21; Chromosome abnormality; Clinical Trials; Confocal Microscopy; Down Syndrome; Epithelial Cells; Exhibits; Exposure to; Foundations; Funding; Future; Genes; Genetic; Goals; Human; Human body; Immunoassay; Immunobiology; Immunoblotting; Individual; Infant; Infection; Inflammatory; Inflammatory Response; Interferon Activation; Interferon Receptor; Interferons; Investigation; Knowledge; Laboratories; Molecular; Molecular Target; Nose; Pathway interactions; Patients; Peptidyl-Dipeptidase A; Poly I-C; Population; Predisposition; Production; Receptor Gene; Research; Respiratory Tract Infections; Risk; Role; SARS coronavirus; Severities; Signal Transduction; Syndrome; Testing; Time; Type 2 Angiotensin II Receptor; United States National Institutes of Health; Up-Regulation; Viral; Viral Respiratory Tract Infection; Virus; Vulnerable Populations; Work; age group; airway epithelium; chemokine; clinically relevant; cytokine; cytokine release syndrome; follow-up; high risk; interferon therapy; mortality; novel; novel strategies; overexpression; prevent; programs; public health relevance; receptor; respiratory infection virus; respiratory virus; response; transcriptome sequencing; transcriptomics

ABSTRACT Down syndrome (DS), also known as trisomy 21, is the most common chromosomal abnormality among live- born infants. DS is associated with a disproportionate high risk for severe viral respiratory infections, a top cause of mortality in this vulnerable population. Nonetheless, the risk of DS patients to develop severe SARS- CoV-2 infections during the COVID-19 pandemic has been remarkably understudied. A major concern in DS individuals the risk to develop hyper-inflammatory responses manifested as cytokine storm and/or multisystem inflammatory syndrome in children. Indeed, people with DS exhibit hyper-activation of interferon (IFN) signaling because they have three copies of the chromosome 21, which encodes four of the six IFN receptors. Importantly, our team and others recently identified that IFNs are strong inducers of the angiotensin-converting enzyme 2 (ACE2), the cell entry receptor of SARS-CoV-2 in the human airway epithelium. The novel finding that SARS-CoV-2 may tap into the host IFN-driven airway epithelial antiviral response to enhance its infectivity represents a paradigm shift for the pathobiology of COVID19, particularly in individuals with DS. The overall goal of this application is to investigate, for the first time, the airway epithelial IFN-driven antiviral and pro- inflammatory responses in young children with DS. Our NIH-funded laboratory (R01HL141237) has the expertise to study the immunobiology of the airway epithelial cell (AEC) of young children, the age group with the highest risk for severe viral respiratory infections. Our central hypothesis is that the airway epithelium of DS children exhibits a dysregulated antiviral molecular program leading to enhanced production of pro-inflammatory cytokines and IFNs (Aim 1); and heightened responsiveness to IFNs leading to overexpression of ACE2 and increased susceptibility to SARS-CoV-2 infection (Aim 2). Defining the key innate cytokines/chemokines and the precise molecular pathways dysregulated in the AEC of DS individuals promises a unique opportunity to discover novel targets to treat severe viral respiratory infections, including SARS-CoV-2. This new knowledge may have long-lasting impact for people with DS by identifying potentially novel approaches to prevent severe respiratory infections caused by SARS-CoV-2 and other viruses (e.g. RSV) in children and adults with DS.

摘要 唐氏综合征（DS），也称为21三体，是生活中最常见的染色体异常。 出生的婴儿。DS与严重病毒性呼吸道感染的不成比例的高风险相关， 这一弱势群体的死亡原因。尽管如此，DS患者发展为严重SARS的风险- COVID-19大流行期间的COV-2感染一直受到严重的研究不足。DS中的一个主要问题 个体发展过度炎症反应的风险，表现为细胞因子风暴和/或多系统 儿童炎症综合征。事实上，患有DS的人表现出干扰素（IFN）信号的过度激活 因为它们有三个21号染色体的拷贝，21号染色体编码六种干扰素受体中的四种。 重要的是，我们的团队和其他人最近发现，干扰素是血管紧张素转换的强诱导剂， 酶2（ACE 2），SARS-CoV-2在人气道上皮中的细胞进入受体。的新发现 SARS-CoV-2可能利用宿主IFN驱动的气道上皮抗病毒反应来增强其感染性 代表COVID 19病理生物学的范式转变，特别是在DS患者中。整体 本申请的目的是首次研究气道上皮干扰素驱动的抗病毒和促增殖作用。 炎症反应的儿童与DS。我们的NIH资助实验室（R 01 HL 141237）拥有 专业知识，研究免疫生物学的气道上皮细胞（AEC）的幼儿，年龄组与 严重病毒性呼吸道感染的风险最高。我们的中心假设是气道上皮 的DS儿童表现出失调的抗病毒分子程序， 促炎细胞因子和IFN（目的1）;以及对IFN的反应性增强，导致 ACE 2过表达和增加对SARS-CoV-2感染的易感性（目的2）。确定主要 先天性细胞因子/趋化因子和DS个体AEC中失调的精确分子途径 有望为发现治疗严重病毒性呼吸道感染的新靶点提供独特的机会， SARS冠状病毒2型。这项新知识可能会对DS患者产生长期影响， 预防SARS-CoV-2和其他病毒引起的严重呼吸道感染的新方法（例如， RSV）的儿童和成人DS。