1 Whereas problematic wheeze is highly prevalent in pre-school children, in most it is a transient syndrome that 2 resolves before school age. However, an important sub-group of wheezy toddlers goes on to develop 3 persistent asthma. Studies have not addressed the inflammatory phenotype present in the lung of high-risk 4 pre-school children at a time before an asthma diagnosis has been established and, perhaps, at a time when 5 interventions could still alter the natural history of their disease. We have evidence suggesting a high 6 prevalence of asymptomatic lower respiratory RV infection in pre-school children who had a clinically indicated 7 diagnostic bronchoscopy for the evaluation of severe recurrent wheeze. These infants also had higher 8 infiltration with eosinophils and elevated concentrations of IL-5 and IL-13 in their BAL fluid. Importantly, these 9 children did not (yet) display characteristic features of childhood asthmatics, including evidence of systemic 10 allergic inflammation – either atopic sensitization or circulating eosinophilia. We will test the hypothesis that 11 in young children, RV infection in the lower respiratory tract defines a phenotype characterized by 12 reduced innate immunity that underlies susceptibility to lower airway infection with RV and contributes 13 to an evolving type 2 lung inflammatory milieu. We propose that in predisposed/at risk children, RV 14 transforms the airway epithelium through epigenetic modification. This transformed epithelium drives the 15 development of type 2 inflammatory responses which are re-stimulated with subsequent viral infections. We 16 will accordingly also show in this proposal that type 2 inflammation is associated with reduced ability to 17 recognize and restrict viral infections. Hence, we propose that a vicious cycle of ever-increasing susceptibility 18 to RV and recurrent infections underlies progressively worsening type 2 inflammation, ultimately leading to the 19 irreversible and inexorable development of asthma. And while we cannot speculate when in development this 20 vicious cycle begins, it is still reasonable to speculate that eradication of the RV component could break this 21 cycle and thereby interrupt the evolution of a transformed epithelium. These results would then provide the 22 basis for intervening with anti-viral therapies to potentially arrest disease progression in these at-risk pre- 23 school children. Specific Aim 1 will initially demonstrate lower airway RV infection and characterize lower 24 respiratory and systemic inflammatory patterns in infected and uninfected infants. We expect to confirm that 25 lung fluid of children with RV infection will demonstrate a type 2 inflammatory environment and that this will be 26 manifest prior to the development of increased peripheral blood eosinophilia or systemic markers of allergen 27 sensitization. Specific Aim 2 will investigate the evolution of a type 2 inflammatory milieu in RV infected 28 chi...