RSV and asthma: Defining host and exposure variation on disease development

项目1摘要-呼吸道合胞病毒与哮喘：确定宿主和暴露变量对疾病的影响 发展 呼吸道合胞病毒(RSV)下呼吸道感染(LRI)持续强烈 与哮喘有关。虽然这一点几十年来一直得到反复证明，但进展相当有限 在进一步了解呼吸道合胞病毒感染和喘息性疾病之间的因果联系方面取得了进展 自该观察首次发表以来，已经有50多年了。在我们之前的融资周期中，我们已经展示了 呼吸道合胞病毒严重感染和哮喘之间的关系被一个共同的基因混淆 对这两种情况都有倾向。我们还证明，婴儿呼吸道合胞病毒感染，不仅严重 感染与哮喘风险增加有关，而在婴儿时期未发现RSV感染显著 预防哮喘的发生。了解呼吸道合胞病毒引起哮喘的途径 发展我们已经证明，婴儿RSV感染改变了发育中的鼻部微生物群和类型 1抗病毒反应，我们已经确定了与哮喘风险增加相关的特定RSV毒株。这 U19更新在这一系列重要发现的基础上进行扩展，以回答关键问题以评估因果关系和 告知有针对性的哮喘预防。我们的主要假设是婴儿呼吸道合胞病毒的年龄相关性效应 感染通过改变呼吸道上皮DNA甲基化(DNaM)而导致慢性呼吸系统疾病。 以及呼吸道上皮新陈代谢和发育规划。此外，我们假设，识别 基因与呼吸道合胞病毒的相互作用将解释婴儿呼吸道合胞病毒感染后哮喘易感性的个体差异。 为了检验这些假设，我们将使用人类自然准随机研究的组合 婴儿呼吸道合胞病毒感染专门用于评估婴儿呼吸道合胞病毒感染对后续 呼吸道健康与呼吸道上皮细胞及呼吸道合胞病毒感染鼻腔上皮细胞的体外模型 细胞(NAECs)。检验这些假设的三个目标的首要目标是：1)确定 婴儿首次感染呼吸道合胞病毒的年龄是否与随后再次发生喘息的风险有关 2)阐明呼吸道合胞病毒对呼吸道上皮细胞分化和分化的纵向影响。 婴儿和儿童的代谢；3)评估宿主基因与婴儿RSV感染的相互作用和 RSV依赖的NAEC dNaM纵向识别RSV依赖的变化和时间稳定性 DNaM评分及其与反复喘息和哮喘的关系。 这一提议有可能极大地促进我们对机制和 呼吸道合胞病毒对反复喘息和哮喘影响的发育过程，并识别新的 预防急性呼吸道合胞病毒发病率、儿童反复喘息和哮喘的有针对性的途径。

PROJECT 1 ABSTRACT - RSV and asthma: Defining the influence of host and exposure variation on disease development Respiratory syncytial virus (RSV) lower respiratory tract infection (LRI) is strongly and consistently associated with asthma. While this has been repeatedly demonstrated for decades, rather limited progress has been made on further understanding the causal association between RSV LRI and wheezing illnesses over the more than 50 years since the observation was first published. In our prior funding cycle we have demonstrated the relationship between a severe infection with RSV and asthma is confounded by a shared genetic predisposition to both conditions. We have also demonstrated that infant RSV infection, not only severe infection, is associated with increased asthma risk, and that missing RSV infection during infancy significantly protects from asthma development. To understand pathways through which RSV contributes to asthma development we have demonstrated that infant RSV infection alters the developing nasal microbiome and type 1 anti-viral responses, and we have identified specific RSV strains associated with increased asthma risk. This U19 renewal expands upon this series of significant findings to answer key questions to assess causality and inform targetable asthma prevention. Our overarching hypothesis is that age-dependent effects of infant RSV infection contribute to chronic respiratory disease through altering airway epithelial DNA methylation (DNAm), and airway epithelial metabolism and developmental programming. Further, we hypothesize that identifying gene x RSV interactions will explain individual variability in asthma susceptibility following infant RSV infection. To test these hypotheses we will use a combination of human natural quasi-randomization studies of infant RSV infection specifically designed to assess the impact of infant RSV infection on subsequent respiratory health and the airway epithelium, and in vitro models of RSV infection of nasal airway epithelial cells (NAECs). The overarching objectives of the 3 aims that will test these hypotheses are: 1) to determine whether the age of first infant RSV infection is associated with risk of subsequent incident recurrent wheeze and asthma; 2) to delineate the longitudinal effects of RSV on airway epithelial cell differentiation and metabolism throughout infancy and childhood; 3) to evaluate host gene ´ infant RSV infection interactions and RSV-dependent NAEC DNAm longitudinally to identify changes and temporal stability of RSV-dependent DNAm marks and their association with recurrent wheeze and asthma. This proposal has the potential to greatly advance our understanding of the mechanisms and developmental processes underlying the effect of RSV on recurrent wheeze and asthma, and to identify novel targetable pathways for prevention of acute RSV morbidity, childhood recurrent wheeze and asthma.