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Bronchial Epithelial Transcriptome Reveals Dysregulated Interferon and InflammatoryResponses to Rhinovirus in Exacerbation-Prone Pediatric Asthma

Naresh Doni Jayavelu,¹ Basilin Benson,¹ Patricia C. dela Cruz,² Weston T. Powell,² Lucille M. Rich,² Elizabeth R. Vanderwall,² Camile R. Gates,² Andrew J. Nagel,³ Maria P. White,² Nyssa B. Samanas,² Kourtnie Whitfield,⁴ Teal S. Hallstrand,⁵ Steven F. Ziegler,¹ Matthew C. Altman,¹ and Jason S. Debley²

Published November 11, 2025 - More info

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-β 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.

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