Respiratory syncytial viral load drives ciliated cell dedifferentiation and suppresses antiviral immunity.

Respiratory syncytial virus (RSV) causes severe lower respiratory disease, yet how it reshapes airway epithelial cells and evades innate immunity remains incompletely understood. We infected adult primary human airway epithelial cultures with RSV and analyzed infected and bystander cells over time using single-cell RNA sequencing and imaging. RSV mainly infected ciliated cells, triggering a virus load-dependent shutdown of genes involved in ciliogenesis, antigen presentation, and innate sensing, including key interferon (IFN) and pattern recognition pathways. Only a subset of infected cells produced type I and III IFNs, while bystander cells exhibited strong IFN-stimulated gene (ISG) signatures. Neither IFN treatment nor ISG induction eliminated infection, but IRF1, an antiviral transcription factor not suppressed by RSV, remained robustly expressed. Ectopic IRF1 expression in vitro reduced viral replication. These findings reveal how RSV evades antiviral defenses and highlight IRF1 as a potential target for therapeutic intervention.