Age-related STAT3 signaling regulates severity of respiratory syncytial viral infection in human bronchial epithelium cells

Respiratory syncytial virus (RSV) causes severe disease mostly in infants; however, mechanisms of age association remain elusive. Here, employing human bronchial epithelium models generated from tracheal aspirate-derived basal stem cells of neonates and adults, we investigate whether age regulates RSV-epithelium interaction to determine disease severity. We show that following RSV infection, only neonatal epithelium model exhibits cytopathy and mucus hyperplasia, and neonatal epithelium has more robust viral spread and inflammatory responses than adult epithelium. Mechanistically, RSV-infected neonatal ciliated cells display age-related impairment of STAT3 activation, rendering susceptibility to apoptosis, which facilitates viral spread. In contrast, SARS-CoV-2 infection of ciliated cells has no effect on STAT3 activation and is not affected by age. Taken together, our findings identify an age-related and RSV-specific interaction with neonatal bronchial epithelium that critically contributes to severity of infection, and STAT3 activation offers a potential strategy to battle severe RSV disease in infants. Overall design: Comparative gene expression profiling analysis of RNA-seq data for basal stem cells from adult and term human tracheal aspirate.