ABSTRACT Infants are more susceptible to morbidity and mortality in response to respiratory virus infections as compared with school age children or adults, but the mechanisms for this clinical observation are not well understood. Vulnerability to respiratory viruses during infancy is likely manifested by an immature lung and immune system. The ability to establish robust protective immunity during infancy is partly limited by developmental shifts in hematopoietic cell function, yet the immune cells that reside within the neonatal lung remain poorly characterized. Even less is known about the epithelial cells of the neonatal lung which could contribute to the immunocompromised state of the human infant given their role in communicating environmental signals to the adaptive immune system. Lastly, how the establishment of commensal bacteria at mucosal sites might influence the immature lung and immune system remains undetermined. Our overall goal is to understand the cellular and molecular mechanisms for increased respiratory disease susceptibility during the first year of life. We will investigate the contribution of primary commensal colonization in the neonatal lung on severity of respiratory virus infection using an infant rhesus monkey model of influenza infection. We hypothesize that primary commensal colonization in the neonatal lung is essential for development of antiviral defense during early life. To test our hypothesis, we will (1) Characterize the influence of primary commensal colonization in the airways on the severity of influenza infection; (2) Investigate how primary commensal colonization directs the ontogeny and functional development of ILC3. (3) Determine if primary commensal colonization alters the intrinsic transcriptome profile of infant airway epithelium. The limitations of early life immunity present formidable obstacles for effective therapeutic strategies that provide protection against respiratory pathogens in the infant. We anticipate that our collaborative effort to study a translational animal model of neonatal development will bring forth new paradigms in understanding mucosal immunity in the infant that have the potential for durable impact on human health.