Dataset Information

Interferon regulatory factor 7 is a major hub connecting interferon-mediated responses in virus-induced asthma exacerbations in vivo.

ABSTRACT:

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.

SUBMITTER: Bosco A

PROVIDER: S-EPMC3246116 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Publications

Interferon regulatory factor 7 is a major hub connecting interferon-mediated responses in virus-induced asthma exacerbations in vivo.

Bosco Anthony A Ehteshami Samira S Panyala Sujatha S Martinez Fernando D FD

The Journal of allergy and clinical immunology 20111123 1

<h4>Background</h4>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.<h4>Objective</h4>The objective of this study was to elucidate the molecular networks that underpin virus-induced exacerbations in asthmatic children in vivo.<h4>Methods</h4>We followed exacerbation-prone asthmatic children prospe ...[more]

PMID: 22112518

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Project description:BackgroundAsthma exacerbations are an important cause of morbidity in asthma. Respiratory infections are often involved in asthma exacerbations in both children and adults. Some individuals with asthma have increased susceptibility to viral infections and as a result increased rates of asthma exacerbations. We sought to identify a transcriptomic signature in the blood associated with asthma exacerbations triggered by respiratory infections (AETRI) and determine its association with increased risk for asthma exacerbations.MethodsWe conducted a two-step study using publicly available, previously generated transcriptomic signatures in peripheral blood mononuclear cells (PBMCs) from asthmatics to identify novel markers of increased risk for asthma exacerbations. In the 1st step, we identified an in vitro PBMC signature in response to rhinovirus. In the 2nd step, we used the in vitro signature to filter PBMC transcripts in response to asthma exacerbations in an independent in vivo cohort. Three different subgroups were identified and studied in the in vivo cohort: 1. Single AETRI; 2. Multiple AETRIs; and 3. Single non-infectious asthma exacerbations. We performed pathway and network analyses in all independent comparisons. We also performed an immunologic gene set enrichment analysis (GSEA) of the comparison between single AETRI and non-infectious asthma exacerbations.ResultsThe in vitro signature identified 4354 differentially expressed genes (DEGs) with a fold change (FC) ≥ 1.2, false discovery rate (FDR) < 0.05. Subsequent analyses filtered by this in vitro signature on an independent cohort of adult asthma identified 238 DEGs (FC≥1.1, FDR < 0.1) in subjects with a single AETRI and no DEGs in single non-infectious asthma exacerbations. A comparison between the response in subjects with single and multiple AETRIs identified two discordant gene subsets. In the largest discordant subset (n = 63 genes) we identified an impaired type I interferon and STAT1 response in multiple AETRIs during the acute phase of the exacerbation and an upregulated STAT1 response at baseline. The STAT1 upregulation at baseline in subjects with multiple AETRIs was accompanied by upregulation of pro-inflammatory molecules including IL-15, interferon-stimulated genes (ISGs), several toll-like receptors 2, - 4, - 5 and - 8 and a triggering receptor expressed on myeloid cells 1 (TREM1) network.ConclusionsSubjects with asthma and multiple AETRIs display a pro-inflammatory signature at baseline, associated with elevated STAT, IL-15 and ISGs, and an impaired STAT1 response during acute asthma exacerbations.

Project description:Human rhinoviruses (HRV) cause the majority of colds and trigger exacerbations of chronic lower airway diseases. Airway epithelial cells are the primary site for HRV infection and replication, and the initiation of host inflammatory responses. At present, the molecular mechanisms that underpin HRV responses in airway epithelial cells are incompletely understood. The aim of this study was to employ microarray profiling, upstream regulator analysis, and siRNA mediated gene silencing to further our understanding of the role of interferon regulatory factor 7 (IRF7) in this response.Primary human bronchial epithelial cells (HBE) where transfected with siRNA that targets IRF7 or a non-silencing control (all-star control) using Lipofectamine. The cells were allowed to recover, and then cultured in the presence or absence of HRV-16 for 24 h. Global patterns of gene expression were profiled on microarrays. A subset of genes identified in the microarray study were validated at the mRNA and/or protein level using real time RT-qPCR, ELISA, and western blots.Hundreds of genes were upregulated in HBE during HRV infection. Pathways analysis demonstrated that these genes were mainly involved in type I and II interferon signaling, RIG-I/MDA5 signaling, antigen processing and presentation, and apoptosis. Upstream regulator analysis of these data suggested that IRF7 was a major molecular driver of this response. Knockdown of IRF7 reduced the HRV-driven upregulation of genes involved in antiviral responses (interferon signaling, Toll-like receptor signaling, NOD-like receptor signaling, RIG-I/MDA5 signaling), and increased the expression of genes that promote inflammation (e.g. CXCL5, IL-33, IL1RL1) and the response to oxidative stress. However, the majority of genes that were perturbed by HRV in HBE cells including those that are known to be regulated by IRF7 were insensitive to IRF7 knockdown. Upstream regulator analysis of the part of the response that was insensitive to IRF7 knockdown suggested it was driven by NF-?B, STAT1, STAT3, and IRF1.Our findings demonstrate that IRF7 regulates the expression of genes involved in antiviral immunity, inflammation, and the response to oxidative stress during HRV infections in HBE cells, and also suggests that other transcription factors play a major role in this response.

Dataset Information

Interferon regulatory factor 7 is a major hub connecting interferon-mediated responses in virus-induced asthma exacerbations in vivo.

Background

Objective

Methods

Results

Conclusions

Publications

Interferon regulatory factor 7 is a major hub connecting interferon-mediated responses in virus-induced asthma exacerbations in vivo.

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