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

项目摘要 SARS-CoV-2在儿童中的感染大多比成人温和，致命性较低。这种较低 还令人惊讶地观察到与SARS-CoV-2相关疾病的发病率 对于哮喘儿童，最常见的慢性呼吸道和炎症性疾病， 孩子随着社会距离和面具的急剧但暂时减少， 常见病毒性呼吸道感染的传播，这产生了显著的积极作用 减少儿童中病毒引发的哮喘。SARS-CoV-2感染的流行率不断上升 在儿童和非SARS-CoV-2呼吸道病毒感染的复苏， 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到来的SARS-CoV-2疫苗的反应。 除了强烈的遗传倾向外，哮喘与病毒性呼吸道疾病密切相关。 感染和感染性刺激可以产生长期的表观遗传后果， 对后续感染的免疫反应。我们认为，一种常见的遗传变异， 哮喘儿童鞘脂水平的改变也可能导致哮喘的发病机制受到限制， SARS-CoV-2在儿童哮喘中的应用这一提议旨在检验假设是否普遍 哮喘中的遗传变异中度年龄依赖性结果和免疫应答 SARS-CoV-2感染和疫苗使用纽约儿童哮喘队列， 在大流行的早期。这个队列是唯一适合的假设，因为它（1）包括儿童 所有年龄段的哮喘和非哮喘;（2）是丰富的儿童从种族，种族， 与健康差异和SARS高暴露率相关的社会经济背景- CoV-2;（3）已经招募了300多人，抗体阳性率很高 自2020年5月以来。关于哮喘和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）和鼻样本的生物标本将 使我们能够解决这三个具体目标，以（1）确定年龄依赖的影响， SARS-CoV-2感染对哮喘儿童呼吸道健康的影响;（2）明确哮喘儿童的 SARS-CoV-2感染对造血干细胞的表观遗传学和转录组学影响， 以及（3）确定常见的遗传性哮喘风险等位基因对SARS-CoV-2应答的影响 鼻上皮细胞感染和随后的呼吸道合胞病毒感染， 鼻病毒这些研究将得到一个具有病毒免疫学专业知识的团队的支持， 儿童哮喘，免疫反应的表观遗传学，并将告知年龄和疾病- SARS-CoV-2和常见呼吸道病毒对儿童的具体影响和机制。

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.