Early-Life Commensal Lung Bacteria Shape Immune Responses and RSV Susceptibility in Neonatal Mice

The lung mucosa at birth and shortly after is particularly vulnerable to respiratory syncytial virus (RSV) infection. Respiratory disease severity is strongly influenced by the age at first exposure, which may also affect the trajectory of airway function. Early-life represents a critical window for lung development and initial microbiota colonization, both of which shape mucosal immune responses to RSV. The impact of the initial establishment of the lung microbiota by its primo-colonizing strains on susceptibility to RSV infection in neonatal mice remains poorly described. In the present study, we showed that early-life primo-colonizing bacterial strains in the mouse lung differentially induce innate immune responses and influence RSV susceptibility in ex vivo models using lung explants and alveolar macrophages (AMs). We identified a specific bacterial strain (strain 17) whose prior exposure enhances type I interferon (IFN-I) responses in AMs upon RSV infection and reduces viral replication both ex vivo and in vivo in lung tissues. Intranasal administration of this strain during early life prevented the development of immunopathological responses upon RSV reinfection in adult mice. Finally, using a translational human airway epithelium model, we demonstrated that pre-exposure to strain 17 restricts RSV spread without cytotoxicity, likely via enhanced {beta}-defensin 2 production. These findings highlight the potential of early-life microbiota modulation as a promising intervention for preventing RSV disease and its long-term respiratory consequences.