Project Summary The long-term objective of this grant is to define the relationship between infant respiratory syncytial virus (RSV) infection and the host response that enables asthma inception using both a longitudinal birth cohort (Project 1) and a mouse model of RSV infection (Project 2). The goals of Project 1 are two-fold: first to identify RSV strains associated with asthma inception, and second to understand the mechanisms through which these RSV strains cause asthma in humans. To test our hypotheses, we propose to extend longitudinal follow-up of the 1900 children enrolled in the established INSPIRE birth cohort who will be four 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 development and the pathways through which these RSV strains cause asthma. We propose to test our hypotheses through the following Aims. Specific Aim 1: Identify RSV strains associated with asthma inception and respiratory morbidity at ages 6 to 8 years. Specific Aim 2: Determine how RSV strains differentially impact the host microbial environment during primary RSV infection, if those microbial changes persist with time, and if microbial changes are associated with changes in immune responses and asthma development. Specific Aim 3: Assess primary airway epithelial cell (AEC) response to asthmagenic RSV strains. We will in vitro identify the differential AEC responses from INSPIRE children with their infecting strains and asthmagenic RSV strains. Specific Aim 4: Determine RSV induced memory T cell and innate responses associated with asthma inception in the INSPIRE cohort. We will use non- asthmagenic (control) and asthmagenic strains of RSV to stimulate PBMCs in children with and without RSV-associated asthma at ages 3 and 6 years, and compare responses. We propose an innovative set of studies identifying asthmagenic RSV strains and elucidating mechanisms of RSV-mediated asthma development by determining how RSV strains interact with the host to cause asthma.