Airway dual-transcriptomics in bronchiolitis and risk of asthma: MARC-35 cohort

细支气管炎是美国婴儿住院的主要原因。然而，它的严重性并不是 传统的风险因素。此外，虽然因细支气管炎住院的婴儿在 非常高的风险事件哮喘，很少有人知道的机制，这两者之间的联系 条件这些主要的知识差距阻碍了发展细支气管炎的努力 治疗策略和预防哮喘在这一高危人群。第35届多中心 气道研究协作组（MARC-35）研究（U01AI087881; Camargo，PI）正在进行中 17-一项中心队列研究，2011年期间入组了1,016名患有细支气管炎的住院婴儿， 2014.在这个种族、民族和地理多样化的队列中，研究人员 收集了高质量的生物标本，包括鼻咽气道样本， 住院随访数据包括一年两次的父母访谈、医疗记录审查， 6岁时进行现场检查，迄今为止随访率> 90%。目前的R01项目将 通过分析这两种基因的基因表达， 鼻咽气道微生物组（元转录组）和宿主反应（转录组） 毛细支气管炎的设置，并通过检查它们与急性（毛细支气管炎严重程度） 和慢性（哮喘发作）结果。在目标1中，我们将研究 气道微生物组谱、宿主转录组谱和毛细支气管炎的急性严重程度。在 目的2，我们将确定气道微生物组和宿主转录组之间的关系， 毛细支气管炎婴儿的特征，以及儿童哮喘的风险。最后，使用 系统生物学方法，目标3将通过整合临床，病毒， 免疫学（例如，IgE）、微生物组（组成和功能）和宿主转录组数据， 并确定它们与急性和慢性结果的关系。我们的试验数据 有力地支持了我们的假设目前的R01项目将提供一个独特的机会， 通过检查毛细支气管炎的功能活性来确定毛细支气管炎的病理生物学 微生物组和气道中的宿主反应。此外，我们还将确定 毛细支气管炎与哮喘的联系机制，通过调查患有毛细支气管炎的婴幼儿 （中位年龄，3个月）-肺发育关键时期的自然实验。的 该项目将为制定有针对性的急性干预措施提供强有力的证据基础 细支气管炎治疗和哮喘初级预防（例如，通过调节微生物组 免疫反应）。研究人员是NIH资助的研究人员， 所有相关领域的专业知识。该研究与2013年NIAID战略计划相吻合。

Bronchiolitis is the leading cause of infant hospitalization in the US. Yet, its acute severity is not explained by traditional risk factors. Additionally, while infants hospitalized for bronchiolitis are at very high risk for incident asthma, little is known about the mechanisms linking these two conditions. These major knowledge gaps have hindered efforts to develop bronchiolitis treatment strategies and to prevent asthma in this high risk population. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01AI087881; Camargo, PI) is an ongoing 17-center cohort study that enrolled 1,016 hospitalized infants with bronchiolitis during 2011- 2014. In this racially-, ethnically-, and geographically-diverse cohort, investigators have collected high-quality biospecimens, including nasopharyngeal airway samples at the index hospitalization. Follow-up data include biannual parent interviews, medical record reviews, and in-person exam at age 6 years, with >90% follow-up to date. The present R01 project would extend this large well-characterized bronchiolitis cohort by profiling the gene expression of both nasopharyngeal airway microbiome (metatranscriptome) and host response (transcriptome) in the setting of bronchiolitis, and by examining their relations to both acute (bronchiolitis severity) and chronic (incident asthma) outcomes. In Aim 1, we will examine the relations among the airway microbiome profiles, host transcriptomic profiles, and acute severity of bronchiolitis. In Aim 2, we will determine the relations among the airway microbiome and host transcriptomic profiles in infants with bronchiolitis, and the risk of developing childhood asthma. Finally, using a systems biology approach, Aim 3 will define bronchiolitis endotypes by integrating clinical, virus, immunology (e.g., IgE), microbiome (composition and function) and host transcriptome data, and determine their associations with both the acute and chronic outcomes. Our pilot data lend compelling support to our hypotheses. The present R01 project will provide a unique opportunity to define the pathobiology of bronchiolitis through examining the functional activity of microbiome and host response in the airway. Furthermore, we will also determine the mechanisms linking bronchiolitis to asthma, by investigating young infants with bronchiolitis (median age, 3 months) – a natural experiment during a critical period of lung development. The project will provide a strong evidence base for developing targeted interventions for acute bronchiolitis treatment and asthma primary prevention (e.g., through modulation of microbiome and immune responses). The investigators are NIH-funded researchers with international expertise in all relevant fields. The study matches well with the 2013 NIAID Strategic Plan.