Influenza virus-induced type I interferons disrupt alveolar epithelial repair and tight junction integrity in the developing lung.

Recently, we demonstrated that influenza A virus (IAV)-infected murine neonates lacking a functional IFN-I receptor (IFNAR^-/-) had significantly improved survival and reduced lung pathology relative to wild-type (WT) neonates. In direct contrast, adult IFNAR^-/- mice display enhanced morbidity following IAV infection relative to WT adults. We hypothesized that IAV-induced IFN-I signaling in primary neonatal type II alveolar epithelial cells (TIIECs), the main cell type of IAV infection and initiator of host response in the lung, contributed to age-specific viral pathogenesis. Multifactorial transcriptional analysis of purified TIIECs revealed age, not infection status, as the primary driver of transcriptional differences in TIIECs. Subsequent pathway analysis demonstrated IAV-infected IFNAR^-/- neonates significantly upregulated cell proliferation, tissue repair and tight junction genes at 2-days post-infection (dpi), compared to WT neonates. Next, to determine if these growth and repair differences persisted later in infection, targeted analysis of repair gene expression and immunofluorescent quantification of pulmonary sealing tight junction molecules ZO-1 and occludin was performed at 6-dpi. Relative to WT neonates, IFNAR^-/- neonates had significantly higher whole lung occludin staining and repair gene expression. Together, our data demonstrates IFN-I signaling is extremely pathogenic in the developing lung by disrupting alveolar repair and pulmonary barrier integrity.