Asthma and lower airway disease
Interferon regulatory factor 7 is a major hub connecting interferon-mediated responses in virus-induced asthma exacerbations in vivo

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Background

Exacerbations are responsible for a substantial burden of morbidity and health care use 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 to 14 days later. Coexpression network analysis and prior knowledge was used to reconstruct the underlying gene networks.

Results

The data showed that an intricate modular program consisting of more than 1000 genes was upregulated during acute exacerbations in comparison with 7 to 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 hyperconnected hub nodes, most notably interferon regulatory factor 7, 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 signaling hubs were identified that could be novel therapeutic targets for asthma attacks.

Section snippets

Study population

The study population consisted of 16 children from a larger prospective study of 218 children with mild-to-moderate asthma who were followed for 18 months or until they had an exacerbation. The protocol design and follow-up have been described previously.9 Briefly, at enrollment, subjects were assessed by a study physician, and if necessary, adjustments were made to achieve national guideline recommendations for asthma control. When a child experienced symptoms of an exacerbation (cough,

Gene expression profiling of virus-induced asthma exacerbations in nasal lavage cells

To investigate the mechanisms underlying asthma exacerbations, children with mild-to-moderate asthma (n = 16) were followed prospectively, and nasal lavage samples were obtained during an acute, picornavirus-induced exacerbation and 7 to 14 days later. The characteristics of the study population are presented in Table I, and it is noteworthy that these were moderate exacerbations defined with criteria equivalent to the American Thoracic Society/European Respiratory Society consensus.15 The

Discussion

Acute exacerbations have a substantial effect on health care use and treatment costs for children with asthma. Although inhaled corticosteroids can reduce the frequency of exacerbations, they cannot entirely prevent them, and they are not effective at controlling neutrophilic inflammation, which is increasingly recognized as playing a major role in pathogenesis.33 New drugs are urgently needed. However, selection of drug targets based on oversimplified, gene/factor-centric paradigms of

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  • Cited by (0)

    Supported by National Institutes of Health grant HL080083. A.B. is the recipient of a Medical Research Fellowship from the Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia.

    Disclosure of potential conflict of interest: F. D. Martinez has consultant arrangements with MedImmune and Bayer. The rest of the authors declare that they have no relevant conflicts of interest.

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