Contoli, M. et al. Role of deficient type III interferon- production in asthma exacerbations. Nat. Med. 12, 1023-1026

Imperial College London, Londinium, England, United Kingdom
Nature Medicine (Impact Factor: 27.36). 10/2006; 12(9):1023-6. DOI: 10.1038/nm1462
Source: PubMed


Rhinoviruses are the major cause of asthma exacerbations, and asthmatics have increased susceptibility to rhinovirus and risk of invasive bacterial infections. Here we show deficient induction of interferon-lambdas by rhinovirus in asthmatic primary bronchial epithelial cells and alveolar macrophages, which was highly correlated with severity of rhinovirus-induced asthma exacerbation and virus load in experimentally infected human volunteers. Induction by lipopolysaccharide in asthmatic macrophages was also deficient and correlated with exacerbation severity. These results identify previously unknown mechanisms of susceptibility to infection in asthma and suggest new approaches to prevention and/or treatment of asthma exacerbations.

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    • "In support of the theory of a relatively ineffective immune system at birth, experimental HRV infection of bronchial epithelial cell tissue cultures of asthmatic children demonstrated deficient IFN-b responses thus facilitating viral replication [63]. Further studies by the same group have demonstrated a similar picture with deficient IFN-l immune responses [64]. Another study demonstrated that IFN-l and IL-10 (Th1 responses) production were associated with less respiratory symptoms while Th2 responses, such as IL-4, IL-5 and IL-13, were associated with increased respiratory symptoms [65]. "
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    ABSTRACT: Human rhinovirus (HRV) infections are now widely accepted as the commonest cause of acute respiratory illnesses (ARIs) in children. Advanced PCR techniques have enabled HRV infections to be identified as causative agents in most common ARIs in childhood including bronchiolitis, acute asthma, pneumonia and croup. However, the long-term implications of rhinovirus infections are less clear. The aim of this review is to examine the relationship between rhinovirus infections and disorders of the lower airways in childhood.
    Full-text · Article · Sep 2014 · Paediatric Respiratory Reviews
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    • "This activity may be of particular importance for immune-mediated lung diseases such as asthma. Indeed, in children with asthma, it was observed that those patients with a minor allele genotype had lower IFNL3 levels in BAL samples, but also significantly higher eosinophil granulocytes in sputa samples with higher Th2 cytokines.162,163,164,165,166 "
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    ABSTRACT: Type-III interferons (IFN-λ, IFNL) are the most recently described family of IFNs. This family of innate cytokines are increasingly being ascribed pivotal roles in host–pathogen interactions. Herein, we will review the accumulating evidence detailing the immune biology of IFNL during viral infection, and the implications of this novel information on means to advance the development of therapies and vaccines against existing and emerging pathogens. IFNLs exert antiviral effects via induction of IFN-stimulated genes. Common single nucleotide polymorphisms (SNPs) in the IFNL3, IFNL4 and the IFNL receptor α-subunit genes have been strongly associated with IFN-α-based treatment of chronic hepatitis C virus infection. The clinical impact of these SNPs may be dependent on the status of viral infection (acute or chronic) and the potential to develop viral resistance. Another important function of IFNLs is macrophage and dendritic cell polarization, which prime helper T-cell activation and proliferation. It has been demonstrated that IFNL increase Th1- and reduce Th2-cytokines. Therefore, can such SNPs affect the IFNL signaling and thereby modulate the Th1/Th2 balance during infection? In turn, this may influence the subsequent priming of cytotoxic T cells versus antibody-secreting B cells, with implications for the breadth and durability of the host response.
    Full-text · Article · Jul 2014 · Emerging Microbes and Infections
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    • "The airway epithelium of asthmatics is characterized by thickening, excessive mucus production and inflammatory cell infiltration [3]. In addition, asthmatic airway epithelium exhibits deficient antiviral and repair responses ex vivo[4,5]. While transcriptional profiling studies have identified the gene expression profiles characterizing these phenotypic differences [6,7], few studies have investigated the involvement of epigenetic mechanisms in the airway epithelium of asthmatics (e.g. "
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    ABSTRACT: Background Mechanisms underlying the development of virus-induced asthma exacerbations remain unclear. To investigate if epigenetic mechanisms could be involved in virus-induced asthma exacerbations, we undertook DNA methylation profiling in asthmatic and healthy nasal epithelial cells (NECs) during Human Rhinovirus (HRV) infection in vitro. Methods Global and loci-specific methylation profiles were determined via Alu element and Infinium Human Methylation 450 K microarray, respectively. Principal components analysis identified the genomic loci influenced the most by disease-status and infection. Real-time PCR and pyrosequencing were used to confirm gene expression and DNA methylation, respectively. Results HRV infection significantly increased global DNA methylation in cells from asthmatic subjects only (43.6% to 44.1%, p = 0.04). Microarray analysis revealed 389 differentially methylated loci either based on disease status, or caused by virus infection. There were disease-associated DNA methylation patterns that were not affected by HRV infection as well as HRV-induced DNA methylation changes that were unique to each group. A common methylation locus stood out in response to HRV infection in both groups, where the small nucleolar RNA, H/ACA box 12 (SNORA12) is located. Further analysis indicated that a relationship existed between SNORA12 DNA methylation and gene expression in response to HRV infection. Conclusions We describe for the first time that Human rhinovirus infection causes DNA methylation changes in airway epithelial cells that differ between asthmatic and healthy subjects. These epigenetic differences may possibly explain the mechanism by which respiratory viruses cause asthma exacerbations.
    Full-text · Article · Jun 2014 · BMC Medical Genomics
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