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

RSV 和哮喘：定义疾病发展的宿主和暴露变异

• 批准号: 10460527
• 负责人: Tina V Hartert
• 金额: $ 36.37万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-04 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460527
• 关键词: Acute; Age; Antiviral Response; Asthma; Biological; Biological Process; Birth; Candidate Disease Gene; Cell Differentiation process; Cellular Metabolic Process; Characteristics; Child; Childhood; Childhood Asthma; DNA Methylation; Data; Data Set; Development; Developmental Process; Disease; Disease Pathway; Epithelial; Epithelial Cells; Etiology; Funding; Genes; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Human; Hypersensitivity; Immune response; In Vitro; Individual; Infant; Infection; Laboratories; Life; Lower Respiratory Tract Infection; Mediation; Mediator of activation protein; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Nose; Outcome; Pathway interactions; Phenotype; Play; Predisposition; Prevention; Process; Publishing; Randomized; Recurrence; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Risk; Role; Series; Sex Differences; Testing; Time; Variant; Viral; Wheezing; age related; airway epithelium; asthma prevention; chronic respiratory disease; complex data; design; early childhood; experimental study; genomic locus; in vitro Model; individual variation; infancy; infant infection; metabolomics; mouse model; nasal microbiome; novel; respiratory health; response; sex; transcriptomics

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.

项目 1 摘要 - RSV 和哮喘：定义宿主和暴露变化对疾病的影响 发展 呼吸道合胞病毒 (RSV) 下呼吸道感染 (LRI) 是强烈且持续的 与哮喘有关。尽管几十年来这一点已被反复证明，但进展相当有限 进一步了解 RSV LRI 与喘息疾病之间的因果关系 自该观察首次发表以来已有 50 多年了。在我们之前的融资周期中，我们已经证明 RSV 严重感染与哮喘之间的关系因共同的遗传基因而混淆 这两种情况的倾向。我们还证明婴儿RSV感染不仅严重 感染，与哮喘风险增加相关，并且婴儿期明显缺失 RSV 感染 防止哮喘发展。了解 RSV 导致哮喘的途径 我们已经证明婴儿 RSV 感染会改变发育中的鼻腔微生物组和类型 1 抗病毒反应，并且我们已经确定了与哮喘风险增加相关的特定 RSV 菌株。这 U19 更新扩展了这一系列重要发现，以回答评估因果关系和 告知有针对性的哮喘预防。我们的首要假设是婴儿 RSV 的年龄依赖性影响 感染通过改变气道上皮 DNA 甲基化 (DNAm) 导致慢性呼吸道疾病， 和气道上皮代谢和发育规划。此外，我们假设识别 基因 x 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，我们将结合人类自然准随机化研究 婴儿RSV感染专门设计用于评估婴儿RSV感染对后续的影响 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）。检验这些假设的 3 个目标的总体目标是： 1) 确定 首例婴儿 RSV 感染的年龄是否与随后发生复发性喘息的风险相关 和哮喘； 2) 描绘RSV对气道上皮细胞分化的纵向影响和 整个婴儿期和儿童期的新陈代谢； 3) 评估宿主基因与婴儿 RSV 感染的相互作用 RSV 依赖性 NAEC DNAm 纵向识别 RSV 依赖性的变化和时间稳定性 DNAm 标记及其与反复喘息和哮喘的关联。 该提案有可能极大地增进我们对机制和机制的理解 RSV 对复发性喘息和哮喘影响的发育过程，并确定新的 预防急性RSV发病、儿童复发性喘息和哮喘的有针对性的途径。