Background
Exacerbations are responsible for a substantial burden of morbidity and health care utilization in children with asthma. Most asthma exacerbations are triggered by viral infections, however, the underlying mechanisms have not been systematically investigated.
Objective
The objective of this study was to elucidate the molecular networks that underpin virus-induced exacerbations in asthmatic children in vivo.
Methods
We followed exacerbation-prone asthmatic children prospectively, and profiled global patterns of gene expression in nasal lavage samples obtained during an acute, moderate, Picornavirus-induced exacerbation, and 7–14 days later. Coexpression network analysis and prior knowledge was employed to reconstruct the underlying gene networks.
Results
The data showed that an intricate, modular program consisting of more than one thousand genes was upregulated during acute exacerbations, in comparison to 7–14 days later. The modules were enriched for coherent cellular processes, including interferon-induced antiviral responses, innate pathogen sensing, response to wounding, small nucleolar RNAs, and the ubiquitin-proteosome and lysosome degradation pathways. Reconstruction of the wiring diagram of the modules revealed the presence of hyper-connected hub nodes, most notably IRF7, which was identified as a major hub linking interferon-mediated antiviral responses.
Conclusions
This study provides an integrated view of the inflammatory networks that are upregulated during virus-induced asthma exacerbations in vivo. A series of innate signalling hubs were identified that could be novel therapeutic targets for asthma attacks.
Asthma exacerbations are associated with subsequent deficits in lung function. Here, we tested the hypothesis that a specific pattern of inflammatory responses during acute exacerbations may be associated with chronic airway obstruction. Gene coexpression networks were characterized in induced sputum obtained during an acute exacerbation, from asthmatic children with or without chronic airflow limitation. The data showed that activation of Th1-like/cytotoxic and interferon signalling pathways during acute exacerbations was decreased in asthmatic children with deficits in baseline lung function. These associations were independent of the identification of picornaviruses in nasal secretions or the use of medications at the time of the exacerbation. Th2-related pathways were also detected in the responses, but variations in these pathways were not related to chronic airways obstruction. Our findings demonstrate that decreased activation of Th1-like/cytotoxic and interferon pathways is a hallmark of acute exacerbation responses in asthmatic children with evidence of chronic airways obstruction.
Asthma exacerbations are associated with subsequent deficits in lung function. Here, we tested the hypothesis that a specific pattern of inflammatory responses during acute exacerbations may be associated with chronic airway obstruction. Gene coexpression networks were characterized in induced sputum obtained during an acute exacerbation, from asthmatic children with or without chronic airflow limitation. The data showed that activation of Th1-like/cytotoxic and interferon signalling pathways during acute exacerbations was decreased in asthmatic children with deficits in baseline lung function. These associations were independent of the identification of picornaviruses in nasal secretions or the use of medications at the time of the exacerbation. Th2-related pathways were also detected in the responses, but variations in these pathways were not related to chronic airways obstruction. Our findings demonstrate that decreased activation of Th1-like/cytotoxic and interferon pathways is a hallmark of acute exacerbation responses in asthmatic children with evidence of chronic airways obstruction.
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