Viral and Host Determinants of Infant and Childhood Allergy and Asthma

摘要 这项应用的长期目标是确定婴儿呼吸道合胞病毒与 呼吸道合胞病毒(RSV)感染和使哮喘发生的宿主反应。有大量证据表明 婴儿期经历严重呼吸道合胞病毒毛细支气管炎的儿童日后发展为哮喘的风险更大。 然而，导致哮喘发生的病毒和宿主决定因素尚不清楚。在……里面 项目1，我们建议延长INSPIRE(婴儿对肺的易感性)的纵向随访 RSV暴露后感染和哮喘)以人口为基础的出生队列中超过1900人 田纳西州婴儿，在第一个U19资助期结束时年满4岁。这将使我们能够 确认我们已确认的RSV毒株是否会导致更严重的婴儿发病率和早期喘息 结果也与哮喘有关，以及这些RSV毒株引起哮喘的途径。 我们建议如下：(1)确定与6至8岁儿童哮喘发病有关的RSV毒株；(2) 确定RSV株在原发RSV感染期间如何影响宿主微生物环境；(3)评估 原代呼吸道上皮细胞(AEC)对引起哮喘的RSV毒株的反应；(4)测定RSV诱导 INSPIRE队列中与哮喘发病相关的免疫反应。在第一个资金周期中，我们有 我是第一个对RSV毒株进行测序和鉴定的小组，这些毒株与显著增加的患病风险有关 反复喘息的结果，以及不同的免疫反应和呼吸道微生物模式。我们 发现感染了带有附着(G)基因突变的RSV毒株的婴儿 序列(2STOP-A4G突变)与毛细支气管炎严重程度评分相比在统计学上显著增加 感染RSV WT基因的婴儿。感染2STOP-A4G突变株正在成为 在人类婴儿中越来越常见，我们小组的研究表明，含有 2Stop-A4G突变在小鼠和人类体内引起Th2先天免疫反应。在项目2中，我们建议 在RSV感染小鼠模型中：(1)确定RSV 2Stop-A4G感染的贡献 2Stop-A4G对原发性毛细支气管炎Th2免疫功能的影响 对吸入空气变应原的免疫反应。确定特定RSV毒株对婴儿的贡献 毛细支气管炎和哮喘的发病机制突出了我们研究的临床意义，并可能提供 疫苗和专注于RSV突变的精准医学方法的治疗目标。

Abstract The long term objective of this application is to define the relationship between infant respiratory syncytial virus (RSV) infection and the host response that enables asthma inception. There is abundant evidence that children who experience severe RSV bronchiolitis during infancy are at greater risk for developing asthma later in childhood; however the viral and host determinants that lead to asthma development are not known. In Project 1, we propose to extend longitudinal follow-up of the INSPIRE (Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure) population based birth cohort of over 1,900 middle Tennessee infants who will be age 4 years at the end of the first U19 funding period. This will enable us to confirm if the RSV strains that we have identified to cause more severe infant morbidity and early wheezing outcomes are also associated with asthma, and the pathways through which these RSV strains cause asthma. We propose the following: (1) Identify RSV strains associated with asthma inception at ages 6 to 8 years; (2) Determine how RSV strains impact the host microbial environment during primary RSV infection; (3) Assess primary airway epithelial cell (AEC) response to asthma-causing RSV strains; (4) Determine RSV induced immune responses associated with asthma inception in the INSPIRE cohort. In the first funding cycle we have been the first group to ever sequence and identify RSV strains associated with significantly increased risk of recurrent wheezing outcomes, as well as differential immune response and airway microbial patterns. We found that infants infected with RSV strains that contained a mutation in the attachment (G) gene end sequence (2stop-A4G mutation) had statistically significantly increased bronchiolitis severity scores compared to infants infected with the RSV WT genotype. Infection with 2stop-A4G mutation strains is becoming increasingly more common in human infants and studies from our group reveal that strains containing the 2stop-A4G mutation cause Th2 innate immune responses in mice and humans. In Project 2, we propose the following in the mouse model of RSV infection: (1) determine the contribution of infection with RSV 2stop-A4G to Th2 immunity in primary bronchiolitis, and (2) determine the contribution of 2stop-A4G to enhanced adaptive immune responses to inhaled aeroallergen. Defining the contribution of specific RSV strains to infant bronchiolitis and asthma pathogenesis highlights the clinical significance of our studies and may provide a therapeutic target for vaccines and precision medicine approaches that focus on RSV mutations.