Bronchial epithelial transcriptome reveals dysregulated interferon and inflammatory responses to rhinovirus in exacerbation-prone pediatric asthma
Naresh Doni Jayavelu, Basilin Benson, Patricia C. dela Cruz, Weston T. Powell, Lucille M. Rich, Elizabeth R. Vanderwall, Camile R. Gates, Andrew J. Nagel, Maria P. White, Nyssa B. Samanas, Kourtnie Whitfield, Teal S. Hallstrand, Steven F. Ziegler, Matthew C. Altman, Jason S. Debley
Naresh Doni Jayavelu, Basilin Benson, Patricia C. dela Cruz, Weston T. Powell, Lucille M. Rich, Elizabeth R. Vanderwall, Camile R. Gates, Andrew J. Nagel, Maria P. White, Nyssa B. Samanas, Kourtnie Whitfield, Teal S. Hallstrand, Steven F. Ziegler, Matthew C. Altman, Jason S. Debley
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Research Article Cell biology Immunology Pulmonology

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

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.

Authors

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

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Figure 1

BECs from children with severe asthma exacerbations show enhanced RV replication and sustained upregulation of IFN and inflammatory and dysregulated metabolic pathways.

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BECs from children with severe asthma exacerbations show enhanced RV rep...
(A) Immunofluorescence image of an asthma donor BEC culture 2 days after RV infection, stained with antibodies against e-cadherin (green), TubA4A (yellow), dsRNA (red). Nuclei stained with DAPI (blue). Arrows indicate replicating virus. Scale bar = 10 µm. (B) GAMM plot showing viral load over time among clinical exacerbation groups and HC. (C) Heat map showing differentially expressed modules identified comparing the SE, NSE, and HC groups. Module expression levels shown as row normalized Z-scores of mean expression for each group and timepoint (columns) with red representing higher relative expression and blue representing lower relative expression. Module row ordering is by hierarchical clustering. The number in parentheses indicates the module number as defined by WGCNA. (D) Scatterplot showing the nonlinear changes in expression of the “Interferon Response” module over time by donor group. Linear regression plot showing association between the “Interferon Response’’ module and viral load by donor group and time post infection (d2-10). (E) Analogous plots of the“Epithelial Remodeling and Inflammation” module demonstrating relationship between module expression and viral load. (F) Analogous plots of the “Stress Response” module demonstrating relationship between module expression and viral load. (G) Analogous plots of the “Cellular Metabolism” module demonstrating relationship between module expression and viral load. (H) Analogous plots of the “Cellular Transcriptional Activity” module demonstrating relationship between module expression and viral load. HC=15 samples from 3 donors, NSE=70 samples from 14 donors, SE=113 samples from 23 donors. Statistics indicate the SE vs NSE GAMM Shape FDR value, SE vs NSE GAMM Avg Estimate and FDR values and the all timepoint linear estimate and FDR values. Fit lines abased on a generalized additive mixed model including 95% confidence intervals.