Project Summary/Abstract Bronchiolitis is the leading cause of hospitalization in US infants. However, the differences in acute severity are not explained by traditional risk factors. In addition, although infants hospitalized with bronchiolitis are at very high risk for incident asthma, the mechanisms linking these two conditions remain unclear. 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 (U01AI-87881; Camargo, PI) is an ongoing 17-center cohort study that completed enrollment of 1016 hospitalized infants with bronchiolitis in 2014. In this diverse cohort (54% African-American or Hispanic), investigators have collected high-quality biospecimens, including nasopharyngeal samples at the index hospitalization (median age, 3 months). 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 current R01 project would extend this large well-characterized bronchiolitis cohort by defining nasopharyngeal airway metagenomic and metabolomic profiles in the setting of bronchiolitis, and by examining their relations to both acute (bronchiolitis severity) and chronic (incident asthma) outcomes in childhood. In Aim 1, we will determine the relations among the airway microbiome (metagenome) profiles, metabolome profiles, and acute bronchiolitis severity. In Aim 2, we will examine the relations among the airway microbiome and metabolomic profiles in infants with bronchiolitis, and the risk of developing asthma. Lastly, using a systems biology approach, Aim 3 will define bronchiolitis endotypes by integrating clinical, virus, molecular data (e.g., airway microbiome and metabolome), and determine their associations with the acute and chronic outcomes. Our pilot data demonstrate compelling support for our hypotheses. The current R01 project will provide a unique opportunity to define the pathobiology of bronchiolitis through examining the functional capacity of microbiome (metagenome) as well as the small molecules representing functional activity of both microbiome and host (metabolome). In addition, by investigating young infants with bronchiolitis – a natural experiment during a crucial period of lung development – we will also define the mechanisms linking bronchiolitis to incident asthma. The study will provide a strong evidence base for bronchiolitis treatment and asthma prevention strategies through the future development of targeted interventions (e.g., modulation of microbiome and metabolic pathways). The investigators are NIH-funded researchers with international expertise in the field. The study matches well with the 2013 NIAID Strategic Plan.