Impact of SARS-CoV-2 infection on respiratory viral immune responses in children with and without asthma

SARS-CoV-2 感染对患有和不患有哮喘的儿童呼吸道病毒免疫反应的影响

• 批准号: 10568344
• 负责人: Stefan Worgall
• 金额: $ 81.23万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568344
• 关键词: 17q21; 2019-nCoV; ATAC-seq; Address; Adult; Affect; Age; Alleles; Antibodies; Asthma; Binding; Blood; COVID-19 outbreak; COVID-19 pandemic; COVID-19 vaccine; Cells; Child; Childhood; Childhood Asthma; Chronic; Clinic; Common Cold Virus; Data; Disease; Enrollment; Epigenetic Process; Epithelial Cells; Ethnic Origin; Frequencies; Gene Expression; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Hematopoietic stem cells; Immune; Immune response; Immunology; Impairment; Incidence; Infection; Inflammasome; Inflammatory; Inflammatory Response; Link; Masks; Membrane; Metabolism; Minor; Monitor; Mucous Membrane; Nasal Epithelium; New York City; Nose; Nuclear; Outcome; Pathogenesis; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Prevalence; Questionnaires; Race; Reaction; Reporting; Respiratory syncytial virus; Rhinovirus; Rhinovirus infection; Risk Factors; SARS-CoV-2 B.1.1.529; SARS-CoV-2 exposure; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; SARS-CoV-2 variant; Sampling; Severities; Shapes; Social Distance; Sphingolipids; Stimulus; T-Lymphocyte; Testing; VDAC1 gene; Vaccines; Variant; Viral; Viral Respiratory Tract Infection; Virus Diseases; Wheezing; age group; age related; airway epithelium; asthma exacerbation; asthmatic; chronic inflammatory disease; chronic respiratory disease; cohort; health disparity; immunoregulation; pandemic disease; pathogenic virus; peripheral blood; post SARS-CoV-2 infection; progenitor; programs; protective effect; receptor expression; respiratory; respiratory health; respiratory infection virus; respiratory pathogen; respiratory virus; response; risk variant; severe COVID-19; single-cell RNA sequencing; socioeconomics; transcriptomics; uptake; 17q21; 2019-nCoV; ATAC-seq; Address; Adult; Affect; Age; Alleles; Antibodies; Asthma; Binding; Blood; COVID-19 outbreak; COVID-19 pandemic; COVID-19 vaccine; Cells; Child; Childhood; Childhood Asthma; Chronic; Clinic; Common Cold Virus; Data; Disease; Enrollment; Epigenetic Process; Epithelial Cells; Ethnic Origin; Frequencies; Gene Expression; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Hematopoietic stem cells; Immune; Immune response; Immunology; Impairment; Incidence; Infection; Inflammasome; Inflammatory; Inflammatory Response; Link; Masks; Membrane; Metabolism; Minor; Monitor; Mucous Membrane; Nasal Epithelium; New York City; Nose; Nuclear; Outcome; Pathogenesis; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Prevalence; Questionnaires; Race; Reaction; Reporting; Respiratory syncytial virus; Rhinovirus; Rhinovirus infection; Risk Factors; SARS-CoV-2 B.1.1.529; SARS-CoV-2 exposure; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; SARS-CoV-2 variant; Sampling; Severities; Shapes; Social Distance; Sphingolipids; Stimulus; T-Lymphocyte; Testing; VDAC1 gene; Vaccines; Variant; Viral; Viral Respiratory Tract Infection; Virus Diseases; Wheezing; age group; age related; airway epithelium; asthma exacerbation; asthmatic; chronic inflammatory disease; chronic respiratory disease; cohort; health disparity; immunoregulation; pandemic disease; pathogenic virus; peripheral blood; post SARS-CoV-2 infection; progenitor; programs; protective effect; receptor expression; respiratory; respiratory health; respiratory infection virus; respiratory pathogen; respiratory virus; response; risk variant; severe COVID-19; single-cell RNA sequencing; socioeconomics; transcriptomics; uptake

PROJECT SUMMARY SARS-CoV-2 infections in children are mostly milder and less lethal than in adults. This lower incidence of relevant disease associated with SARS-CoV-2 has surprisingly also been observed for children with asthma, the most common chronic respiratory and inflammatory disease in children. As social distancing and masks have dramatically but temporarily decreased the spread of common viral respiratory infections, this created the positive effect of a significant decrease of viral-triggered asthma in children. The growing prevalence of SARS-CoV-2 infection in children and the resurgence of non-SARS-CoV-2 respiratory viral infections make it critical and timely to understand how SARS-CoV-2 infection shapes respiratory outcomes and immune responses to other respiratory viruses and the upcoming SARS-CoV-2 vaccines. In addition to a strong genetic predisposition, asthma is strongly linked to viral respiratory infections, and infectious stimuli can have long-term epigenetic consequences that shape immune responses to subsequent infections. We propose that a common genetic variation that alters sphingolipid levels in children with asthma may also result in limited pathogenesis of SARS-CoV-2 in children with asthma. This proposal aims to test the hypothesis is that common genetic variation in asthma moderate age-dependent outcomes and immune responses to SARS-CoV-2 infection and vaccines utilizing an NYC pediatric asthma cohort that was started early in the pandemic. This cohort is uniquely suited to the hypothesis as it (1) includes children of all ages with and without asthma; (2) is enriched for children from ethnic, racial, and socioeconomic backgrounds associated with health disparities and high exposure to SARS- CoV-2; and (3) has already enrolled more than three hundred with a high antibody positivity rate since May 2020. The availability of detailed questionnaire data on asthma and SARS-CoV-2 exposure, biospecimen that include blood (including stored PBMC), and nasal samples will enable us to address these three Specific Aims, to (1) determine the age-dependent effect of SARS-CoV-2 infection on subsequent respiratory health in asthmatic children; (2) define the epigenetic and transcriptomic effect of SARS-CoV-2 infection on hematopoietic stem cells, and (3) define the effects of common genetic asthma risk alleles on responses to SARS-CoV-2 infection of nasal epithelial cells and subsequent infection with respiratory syncytial virus and rhinovirus. These studies will be supported by a team with expertise in viral immunology, pediatric asthma, and epigenetics of immune responses and will inform on age- and disease- specific impact and mechanisms of SARS-CoV-2 and common respiratory viruses in children.

项目摘要 儿童的SARS-COV-2感染大多比成年人更温和，致命。这较低 同时也观察到了与SARS-COV-2相关疾病的发病率 对于患有哮喘的儿童，是最常见的慢性呼吸和炎症性疾病 孩子们。随着社会距离和面具的巨大，但暂时降低了 普通病毒呼吸道感染的传播，这产生了重要的积极作用 儿童病毒触发的哮喘的减少。 SARS-COV-2感染的越来越多 在儿童和非SARS-COV-2呼吸道病毒感染的复兴使其至关重要 并及时了解SARS-COV-2感染如何形成呼吸结局和免疫 对其他呼吸道病毒的反应以及即将推出的SARS-COV-2疫苗。 除了强大的遗传易感性外，哮喘与病毒呼吸道有密切相关 感染和传染性刺激可能会产生长期的表观遗传后果 对随后感染的免疫反应。我们提出了一种常见的遗传变异 改变哮喘儿童的鞘脂水平也可能导致有限的发病机理 哮喘儿童的SARS-COV-2。该提议旨在检验该假设是共同的 哮喘中度依赖年龄的结果和对免疫反应的遗传变异 SARS-COV-2感染和疫苗利用启动的NYC儿科哮喘同类 在大流行的早期。该队列非常适合该假设（1）包括儿童 在有和没有哮喘的所有年龄段； （2）对来自种族，种族和种族和种族和种族的儿童进行了丰富 与健康差异相关的社会经济背景和高度接触SARS- COV-2; （3）已经招募了三百多个抗体阳性率 自2020年5月以来。有关哮喘和SARS-COV-2的详细问卷数据的可用性 暴露，包括血液（包括储存的PBMC）和鼻样样本的生物孔子。 使我们能够解决这三个特定目标，以（1）确定年龄依赖的效果 SARS-COV-2感染哮喘儿童随后的呼吸健康； （2）定义 SARS-COV-2感染对造血干细胞的表观遗传和转录组作用， （3）定义常见遗传哮喘风险等位基因对SARS-COV-2的反应的影响 鼻皮细胞感染，随后感染呼吸道合胞病毒和 鼻病毒。这些研究将得到具有病毒免疫学专业知识的团队的支持， 儿科哮喘和免疫反应的表观遗传学，并将告知年龄和疾病 - SARS-COV-2和儿童常见呼吸道病毒的特定影响和机制。