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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的唐氏综合症（DS），也称为 21 三体症，是活体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高风险相关，这是最重要的这一弱势群体的死亡原因。尽管如此，DS 患者发展为严重 SARS 的风险对 COVID-19 大流行期间的 CoV-2 感染的研究明显不足。 DS 中的一个主要问题个体存在发生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，DS 患者表现出干扰素 (IFN) 信号的过度激活因为它们具有 21 号染色体的三个拷贝，该染色体编码 6 种 IFN 受体中的 4 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 (ACE2)，人类气道上皮中 SARS-CoV-2 的细胞进入受体。新颖的发现 SARS-CoV-2 可能会利用宿主 IFN 驱动的气道上皮抗病毒反应来增强其传染性代表了 COVID19 病理学的范式转变，特别是在 DS 患者中。整体本申请的目标是首次研究气道上皮 IFN 驱动的抗病毒和促病毒药物 DS 幼儿的炎症反应。我们的 NIH 资助实验室 (R01HL141237) 拥有研究幼儿气道上皮细胞（AEC）免疫生物学的专业知识，年龄组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 儿童表现出抗病毒分子程序失调，从而导致促炎细胞因子和干扰素（目标 1）；以及对干扰素的反应性增强，导致 ACE2 过度表达并增加对 SARS-CoV-2 感染的易感性（目标 2）。定义键 DS 个体 AEC 中先天细胞因子/趋化因子和精确分子通路失调有望提供一个独特的机会来发现治疗严重病毒性呼吸道感染的新靶点，包括 SARS-CoV-2。通过识别潜在的 DS 患者，这一新知识可能会对 DS 患者产生长期影响。预防 SARS-CoV-2 和其他病毒（例如病毒）引起的严重呼吸道感染的新方法 RSV）适用于患有 DS 的儿童和成人。