Viral and Host Determinants of Infant and Childhood Allergy and Asthma

摘要 本申请的长期目标是确定婴儿呼吸道合胞病毒与呼吸道感染之间的关系。 (RSV)感染和宿主反应，使哮喘发病。有大量证据表明 在婴儿期经历严重RSV细支气管炎的儿童以后患哮喘的风险更大 在儿童时期;然而，导致哮喘发展的病毒和宿主决定因素尚不清楚。在 项目1，我们建议延长INSPIRE（婴儿肺动脉高压易感性）的纵向随访， RSV暴露后的感染和哮喘）基于人群的出生队列， 田纳西州的婴儿谁将在第一个U19资助期结束时4岁。这将使我们能够 确认我们已经确定的RSV毒株是否会导致更严重的婴儿发病率和早期喘息 结果也与哮喘以及这些RSV株引起哮喘的途径有关。 我们提出以下建议：（1）确定与6至8岁哮喘发病相关的RSV毒株;（2） 确定RSV毒株在原发性RSV感染期间如何影响宿主微生物环境;（3）评估 原代气道上皮细胞（AEC）对引起哮喘的RSV株的反应;（4）确定RSV诱导的 INSPIRE队列中与哮喘发病相关的免疫反应。在第一个融资周期， 他们是第一个测序和鉴定与显著增加的 反复喘息的结果，以及不同的免疫反应和气道微生物模式。我们 发现婴儿感染了RSV病毒株，该病毒株在附着（G）基因末端含有突变， 序列（2stop-A4 G突变）的毛细支气管炎严重程度评分在统计学上显著高于 感染RSV WT基因型的婴儿。2stop-A4 G突变株感染正在成为 在人类婴儿中越来越常见，我们小组的研究表明， 2stop-A4 G突变引起小鼠和人的Th 2先天性免疫应答。在项目2中，我们建议 在RSV感染的小鼠模型中：（1）确定RSV 2stop-A4 G感染的贡献 （2）确定2stop-A4 G对原发性细支气管炎中Th 2免疫的影响，以及（3）确定2stop-A4 G对原发性细支气管炎中Th 2免疫的影响。 吸入过敏原的免疫反应定义特定RSV毒株对婴儿的影响 毛细支气管炎和哮喘发病机制突出了我们研究的临床意义，并可能提供一个 疫苗的治疗靶点和专注于RSV突变的精准医学方法。

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.