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

项目1摘要- RSV和哮喘：确定宿主和暴露变异对疾病的影响 发展 呼吸道合胞病毒（RSV）下呼吸道感染（LRI）是一种强烈且持续的 与哮喘有关。虽然几十年来一再证明这一点，但进展相当有限， 在进一步了解RSV LRI和喘息性疾病之间的因果关系的基础上， 这一观察结果首次发表已有50多年。在上一个融资周期中， RSV严重感染和哮喘之间的关系被一种共同的遗传因素所混淆， 对这两种情况的易感性。我们还证明，婴儿RSV感染，不仅严重， 感染与哮喘风险增加有关，婴儿期缺失RSV感染显著 防止哮喘的发展。了解RSV导致哮喘的途径 我们已经证明，婴儿RSV感染改变了发育中的鼻微生物组和类型， 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更新扩展了这一系列重要发现，以回答评估因果关系的关键问题， 提供有针对性的哮喘预防信息。我们的总体假设是，婴儿RSV的年龄依赖性效应 感染通过改变气道上皮DNA甲基化（DNAm）， 以及气道上皮代谢和发育程序。此外，我们假设， 基因× RSV相互作用将解释婴儿RSV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化研究的组合， 婴儿RSV感染，专门设计用于评估婴儿RSV感染对后续 呼吸健康和气道上皮，以及鼻气道上皮RSV感染的体外模型 细胞（NAEC）。测试这些假设的三个目标的总体目标是：1）确定 婴儿首次感染RSV的年龄是否与随后发生复发性喘息的风险相关 和哮喘; 2）描述RSV对气道上皮细胞分化的纵向影响， 3）评估宿主基因与婴儿RSV感染的相互作用， RSV依赖性NAEC DNA纵向鉴定RSV依赖性NAEC DNA的变化和时间稳定性 DNA标记及其与反复喘息和哮喘的关系 这一建议有可能大大促进我们对机制的理解， RSV对反复喘息和哮喘的影响的潜在发展过程，并确定新的 预防急性RSV发病、儿童复发性喘息和哮喘的靶向途径。

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.