Transcriptomic Profiling of Bronchial Epithelium Reveals Dysregulated Interferon and Inflammatory Responses to Rhinovirus in Exacerbation-Prone Pediatric Asthma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE309705 | GEO | 2025/10/30
REPOSITORIES: GEO
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Project description: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.
2025-10-30 | GSE309698 | GEO
Project description: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.
2025-10-30 | GSE309311 | GEO
Project description:Transcriptomic Profiling of Bronchial Epithelium Reveals Dysregulated Interferon and Inflammatory Responses to Rhinovirus in Exacerbation-Prone Pediatric Asthma
| PRJNA1336771 | ENA
Project description:Transcriptomic Profiling of Bronchial Epithelium Reveals Dysregulated Interferon and Inflammatory Responses to Rhinovirus in Exacerbation-Prone Pediatric Asthma [scRNA-Seq]
| PRJNA1335129 | ENA
Project description:Transcriptomic Profiling of Bronchial Epithelium Reveals Dysregulated Interferon and Inflammatory Responses to Rhinovirus in Exacerbation-Prone Pediatric Asthma [RNA-Seq]
| PRJNA1336779 | ENA
Project description:Patients who are prone to exacerbations of asthma experience significant costs in terms of missed work and school, acute care visits, and hospitalizations. Exacerbations are largely driven by environmental exposures including pollutants, stress, and viral and bacterial pathogens. These exposures are most likely to induce acute severe "asthma attacks" in high-risk patients. These personal risk factors for exacerbations can vary with the phenotype of asthma and age of the patient. In children, allergic sensitization is a strong risk factor, especially for those children who develop sensitization early in life. Airway inflammation is an important risk factor, and biomarkers are under evaluation for utility in detecting eosinophilic and type 2 inflammation and neutrophilic inflammation as indicators of risk for recurrent exacerbations. Insights into inflammatory mechanisms have led to new approaches to prevent exacerbations using mAb-based biologics that target specific type 2 pathways. Challenges remain in developing an evidence base to support precision interventions with these effective yet expensive therapies, and in determining whether these treatments will be safe and effective in young children. Unfortunately, there has been less progress in developing treatments for acute exacerbations. Hopefully, greater understanding of mechanisms relating airway viruses, bacteria, mucin production, and neutrophilic inflammatory responses will lead to additional treatment options for patients experiencing acute exacerbations.
| S-EPMC6942520 | biostudies-literature
Project description:BackgroundBoth anti-viral and anti-inflammatory bronchial effects are warranted to treat viral infections in asthma. We sought to investigate if imiquimod, a TLR7 agonist, exhibits such dual actions in ex vivo cultured human bronchial epithelial cells (HBECs), targets for SARS-CoV-2 infectivity.ObjectiveTo investigate bronchial epithelial effects of imiquimod of potential importance for anti-viral treatment in asthmatic patients.MethodsEffects of imiquimod alone were examined in HBECs from healthy (N=4) and asthmatic (N=18) donors. Mimicking SARS-CoV-2 infection, HBECs were stimulated with poly(I:C), a dsRNA analogue, or SARS-CoV-2 spike-protein 1 (SP1; receptor binding) with and without imiquimod treatment. Expression of SARS-CoV-2 receptor (ACE2), pro-inflammatory and anti-viral cytokines were analyzed by RT-qPCR, multiplex ELISA, western blot, and Nanostring and proteomic analyses.ResultsImiquimod reduced ACE2 expression at baseline and after poly(I:C) stimulation. Imiquimod also reduced poly(I:C)-induced pro-inflammatory cytokines including IL-1β, IL-6, IL-8, and IL-33. Furthermore, imiquimod increased IFN-β expression, an effect potentiated in presence of poly(I:C) or SP1. Multiplex mRNA analysis verified enrichment in type-I IFN signaling concomitant with suppression of cytokine signaling pathways induced by imiquimod in presence of poly(I:C). Exploratory proteomic analyses revealed potentially protective effects of imiquimod on infections.ConclusionImiquimod triggers viral resistance mechanisms in HBECs by decreasing ACE2 and increasing IFN-β expression. Additionally, imiquimod improves viral infection tolerance by reducing viral stimulus-induced epithelial cytokines involved in severe COVID-19 infection. Our imiquimod data highlight feasibility of producing pluripotent drugs potentially suited for anti-viral treatment in asthmatic subjects.
| S-EPMC8688760 | biostudies-literature
Project description:BackgroundThe asthma of some children remains poorly controlled, with recurrent exacerbations despite treatment with inhaled corticosteroids. Aside from prior exacerbations, there are currently no reliable predictors of exacerbation-prone asthma in these children and only a limited understanding of the potential underlying mechanisms.ObjectiveWe sought to quantify small molecules in the plasma of children with exacerbation-prone asthma through mass spectrometry-based metabolomics. We hypothesized that the plasma metabolome of these children would differ from that of children with non-exacerbation-prone asthma.MethodsPlasma metabolites were extracted from 4 pediatric asthma cohorts (215 total subjects, with 41 having exacerbation-prone asthma) and detected with a mass spectrometer. High-confidence annotations were retained for univariate analysis and were confirmed by a sensitivity analysis in subjects receiving high-dose inhaled corticosteroids. Metabolites that varied by cohort were excluded. MetaboAnalyst software was used to identify pathways of interest. Concentrations were calculated by reference standardization.ResultsWe identified 32 unique, cohort-independent metabolites that differed in children with exacerbation-prone asthma compared to children with non-exacerbation-prone asthma. Comparison of metabolite concentrations to literature-reported values for healthy children revealed that most metabolites were decreased in both asthma groups, but more so in exacerbation-prone asthma. Pathway analysis identified arginine, lysine, and methionine pathways as most impacted.ConclusionsSeveral plasma metabolites are perturbed in children with exacerbation-prone asthma and are largely related to arginine, lysine, and methionine pathways. While validation is needed, plasma metabolites may be potential biomarkers for exacerbation-prone asthma in children.
| S-EPMC9825634 | biostudies-literature
Project description: Not available
| S-EPMC7365359 | biostudies-literature
Project description:BackgroundHistamine-releasing factor (HRF) is implicated in allergic diseases. We previously showed its pathogenic role in murine models of asthma.ObjectiveWe aim to present data analysis from 3 separate human samples (sera samples from asthmatic patients, nasal washings from rhinovirus [RV]-infected individuals, and sera samples from patients with RV-induced asthma exacerbation) and 1 mouse sample to investigate correlates of HRF function in asthma and virus-induced asthma exacerbations.MethodsTotal IgE and HRF-reactive IgE/IgG as well as HRF in sera from patients with mild/moderate asthma or severe asthma (SA) and healthy controls (HCs) were quantified by ELISA. HRF secretion in culture media from RV-infected adenovirus-12 SV40 hybrid virus transformed human bronchial epithelial cells and in nasal washings from experimentally RV-infected subjects was analyzed by Western blotting. HRF-reactive IgE/IgG levels in longitudinal serum samples from patients with asthma exacerbations were also quantified.ResultsHRF-reactive IgE and total IgE levels were higher in patients with SA than in HCs, whereas HRF-reactive IgG (and IgG1) level was lower in asthmatic patients versus HCs. In comparison with HRF-reactive IgElow asthmatic patients, HRF-reactive IgEhigh asthmatic patients had a tendency to release more tryptase and prostaglandin D2 on anti-IgE stimulation of bronchoalveolar lavage cells. RV infection induced HRF secretion from adenovirus-12 SV40 hybrid virus transformed bronchial epithelial cells, and intranasal RV infection of human subjects induced increased HRF secretion in nasal washes. Asthmatic patients had higher levels of HRF-reactive IgE at the time of asthma exacerbations associated with RV infection, compared with those after the resolution. This phenomenon was not seen in asthma exacerbations without viral infections.ConclusionsHRF-reactive IgE is higher in patients with SA. RV infection induces HRF secretion from respiratory epithelial cells both in vitro and in vivo. These results suggest the role of HRF in asthma severity and RV-induced asthma exacerbation.
| S-EPMC10917146 | biostudies-literature