RSV Viral Load Drives Ciliated Cell Dedifferentiation and Suppresses Antiviral Immunity in Human Airway Cultures

Respiratory Syncytial Virus (RSV) is a major cause of severe lower respiratory disease, especially in infants and older adults. Despite its prevalence, the precise mechanisms by which RSV remodels airway epithelial cells and evades the host's innate immunity remain incompletely understood. Current vaccines are limited, highlighting the need for a deeper understanding of RSV pathogenesis to identify novel therapeutic targets and improve patient outcomes.

Researchers infected adult primary human airway epithelial cultures with RSV and monitored both infected and bystander cells over time. They employed single-cell RNA sequencing and imaging techniques to analyze cellular changes and gene expression profiles. The study focused on understanding how RSV reshapes airway epithelial cells and influences innate immune responses, comparing gene expression in cells with varying viral loads.

RSV predominantly infected ciliated cells, leading to a virus load-dependent suppression of genes critical for ciliogenesis, antigen presentation, and innate sensing. This suppression included key interferon (IFN) and pattern recognition pathways. Only a subset of infected cells produced type I and III IFNs, while neighboring bystander cells exhibited robust IFN-stimulated gene (ISG) signatures. Neither exogenous IFN treatment nor endogenous ISG induction successfully eliminated the infection. > However, IRF1, an antiviral transcription factor, remained robustly expressed and was not suppressed by RSV, with ectopic IRF1 expression in vitro reducing viral replication.