Abstract The long term objective of this application is to define the relationship between infant respiratory syncytial virus (RSV) infection and the host response that enables asthma inception. There is abundant evidence that children who experience severe RSV bronchiolitis during infancy are at greater risk for developing asthma later in childhood; however the viral and host determinants that lead to asthma development are not known. In Project 1, we propose to extend longitudinal follow-up of the INSPIRE (Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure) population based birth cohort of over 1,900 middle Tennessee infants who will be age 4 years at the end of the first U19 funding period. This will enable us to confirm if the RSV strains that we have identified to cause more severe infant morbidity and early wheezing outcomes are also associated with asthma, and the pathways through which these RSV strains cause asthma. We propose the following: (1) Identify RSV strains associated with asthma inception at ages 6 to 8 years; (2) Determine how RSV strains impact the host microbial environment during primary RSV infection; (3) Assess primary airway epithelial cell (AEC) response to asthma-causing RSV strains; (4) Determine RSV induced immune responses associated with asthma inception in the INSPIRE cohort. In the first funding cycle we have been the first group to ever sequence and identify RSV strains associated with significantly increased risk of recurrent wheezing outcomes, as well as differential immune response and airway microbial patterns. We found that infants infected with RSV strains that contained a mutation in the attachment (G) gene end sequence (2stop-A4G mutation) had statistically significantly increased bronchiolitis severity scores compared to infants infected with the RSV WT genotype. Infection with 2stop-A4G mutation strains is becoming increasingly more common in human infants and studies from our group reveal that strains containing the 2stop-A4G mutation cause Th2 innate immune responses in mice and humans. In Project 2, we propose the following in the mouse model of RSV infection: (1) determine the contribution of infection with RSV 2stop-A4G to Th2 immunity in primary bronchiolitis, and (2) determine the contribution of 2stop-A4G to enhanced adaptive immune responses to inhaled aeroallergen. Defining the contribution of specific RSV strains to infant bronchiolitis and asthma pathogenesis highlights the clinical significance of our studies and may provide a therapeutic target for vaccines and precision medicine approaches that focus on RSV mutations.