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Bronchial epithelial transcriptome reveals dysregulated interferon and inflammatory responses to rhinovirus in exacerbation-prone pediatric asthma

N. Doni Jayavelu,Basilin Benson,P.C. Dela Cruz,Weston T. Powell,Lucille M. Rich,E. Vanderwall,C. Gates,Andrew J Nagel,M. White,Nyssa B. Samanas,Kourtnie Whitfield,T. Hallstrand,Steven F. Ziegler,Matthew C. Altman,Jason S. Debley

Published 2025 in JCI Insight

ABSTRACT

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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