O7‐4: Early life respiratory infections perturb lung function in adulthood

Background and Aim: Environmental exposures in early-life can alter developmental trajectories and induce long-term changes in physiological function. To explore this issue, we developed a mouse model of respiratory viral infection, in which infected neonates have impaired lung function as adults. The aim of this study was to identify virus-induced perturbations to pulmonary gene networks that are linked to developmental and physiological changes. Research Method: BALB/c pups were inoculated with Influenza A/Mem/1/71 (Mem71), Influenza A/PR/1/8 (PR8) or relevant control at seven days of life. Pups were sacrificed and lung tissue was collected for every treatment group at day 7, 14 and 28 post-infection for RNA-seq analysis. Remaining pups grew to adulthood when lung function and responsiveness to methacholine (MCh) were assessed. Results: Prior infection with either Influenza A/PR/1/8 or A/Mem/1/71 resulted in mice being significantly more responsive to MCh as adults with respect to airway resistance, compared with uninfected controls. Cluster analysis of RNA-Seq profiles demonstrated that PR8 perturbed pulmonary gene expression patterns at seven days' post-infection, and whilst these changes waned over time, they persisted to day 28 post-infection. Mem71 infection produced a perturbation of pulmonary gene expression in comparison to PR8. Conclusions: We showed that neonatal respiratory viral infection can impact lung development and ensuing physiological function in adulthood, and this was reflected in the patterns of the underlying gene networks. Our experimental mouse model can be leveraged to understand the molecular mechanisms and principles that link early-life exposures with phenotypic development.