Transcriptomic Profiling of Bronchial Epithelium Reveals Dysregulated Interferon and Inflammatory Responses to Rhinovirus in Exacerbation-Prone Pediatric Asthma [RNA-Seq]

Host factors influencing susceptibility to rhinovirus-induced asthma exacerbations remain poorly characterized. Using organotypic bronchial epithelial cultures from well-characterized children with asthma and healthy children, this study investigated viral load kinetics and resultant host responses by bulk and single-cell transcriptomics and targeted protein analyses. Bronchial epithelium from exacerbation-prone children exhibited greater rhinovirus replication and a cascade of exaggerated downstream interferon (IFN), inflammatory, epithelial stress, and remodeling responses. These transcriptional patterns were confirmed and further refined using single-cell transcriptomics, revealing cell type-specific contributions—particularly from non-ciliated cell populations including secretory immune response, tuft, and basal cells. We observed that these post-infection differences were associated with lower pre-infection IFN-stimulated gene (ISG) expression and protein levels of the ISG CXCL10. Prophylactic IFN-ß treatment reduced viral replication and normalized downstream responses, supporting low baseline (pre-infection) IFN tone as a modifiable causal determinant of host susceptibility to adverse rhinovirus-induced responses in exacerbation-prone children with asthma. Overall design: Bronchial epithelial cells (BECs) from children with asthma (n=37) and healthy children (n=3) ages 6-18 years of age were obtained from subjects while under general anesthesia for an elective surgery using 4-mm Harrell unsheathed bronchoscope cytology brushes (CONMED®) inserted through an endotracheal tube as we have previously described (8, 42). RNA was collected from BEC cultures pre-infection and at 2d, 4d, 7d, and 10d post RV infection.