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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要儿童感染 SARS-CoV-2 的情况大多较成人轻，致死率也较低。这个较低令人惊讶的是，还观察到了与 SARS-CoV-2 相关的相关疾病的发病率对于患有哮喘的儿童来说，这是最常见的慢性呼吸道和炎症性疾病孩子们。由于社交距离和口罩极大但暂时地减少了常见病毒性呼吸道感染的传播，这产生了显着的积极影响减少儿童病毒引发的哮喘。 SARS-CoV-2 感染流行率不断上升儿童和非 SARS-CoV-2 呼吸道病毒感染的死灰复燃使其变得至关重要及时了解 SARS-CoV-2 感染如何影响呼吸系统结果和免疫对其他呼吸道病毒和即将推出的 SARS-CoV-2 疫苗的反应。除了强烈的遗传倾向外，哮喘还与呼吸道病毒密切相关。感染和感染刺激可能会产生长期的表观遗传后果，从而塑造对后续感染的免疫反应。我们提出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制哮喘儿童中的 SARS-CoV-2。该提案旨在检验以下假设：哮喘的遗传变异中等年龄依赖性结果和免疫反应利用纽约市儿科哮喘队列研究 SARS-CoV-2 感染和疫苗疫情初期。该群体特别适合该假设，因为它 (1) 包括儿童患有或不患有哮喘的所有年龄段的人； (2) 丰富了不同民族、种族和群体的儿童与健康差异和高度接触 SARS 相关的社会经济背景冠状病毒-2； (3) 已入组三百余人，抗体阳性率较高自 2020 年 5 月起。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）和鼻腔样本在内的生物样本将使我们能够实现这三个具体目标，（1）确定年龄依赖性的影响 SARS-CoV-2 感染对哮喘儿童后续呼吸道健康的影响； (2) 定义 SARS-CoV-2感染对造血干细胞的表观遗传学和转录组学影响， (3) 定义常见遗传性哮喘风险等位基因对 SARS-CoV-2 反应的影响鼻上皮细胞感染和随后呼吸道合胞病毒感染鼻病毒。这些研究将得到病毒免疫学专业团队的支持，小儿哮喘和免疫反应的表观遗传学，并将提供有关年龄和疾病的信息 SARS-CoV-2 和常见呼吸道病毒对儿童的具体影响和机制。