Repeated Rhinovirus infections drive epigenetic memory and senescence

Background: Recurrent human rhinovirus (HRV) infections in early life are strongly associated with the development of childhood asthma. Repeated viral exposure may induce trained innate immunity (TRIM) through epigenetic reprogramming, while asthma onset has also been linked to accelerated epigenetic aging (DNAge). Our previous findings showed that repeated HRV infections drive loss of epithelial stemness and features of premature aging, raising questions about how TRIM, epithelial regeneration, stemness and aging intersect in airway disease. Objective: To determine how recurrent HRV infections influence epithelial stemness and aging independently of TRIM-related inflammatory responses. Methods: Bronchial epithelial cells (BEAS-2B) were subjected to repeated HRV16 infections. At 24 hours post-infection, cells were harvested for DNA and RNA analyses and reseeded for up to five sequential infections. In parallel, nasal epithelial cells (NECs) from HRV16-infected asthmatic children (ALLIANCE cohort) were analyzed using DNA methylation profiling and RNA sequencing. Results: In BEAS-2B cells, repeated HRV infection led to a significant reduction in the early progenitor marker TP63 (p