Deficient interferon in virus‐induced asthma exacerbations

Respiratory viral infections account for the majority of asthma exacerbations in both adults and children, and are therefore responsible for a large part of the morbidity, mortality and disease burden associated with asthma. Human rhinovirus (RV), an agent commonly associated with the common cold, is the main virus associated with asthma exacerbations, responsible for up to 80% of virus-induced asthma exacerbations [1, 2]. Asthma exacerbations are also not adequately controlled by corticosteroid-based treatments, the mainstay of asthma therapy [3], and finding better treatment alternatives or new therapeutic targets is a main research focus for the future. Recently, much has been learnt regarding the pathogenesis of respiratory viral infections and how this may impact on asthmatic individuals. In a study of co-habiting asthmatic and non-asthmatic couples, Corne et al. demonstrated that while asthmatic and non-asthmatic individuals had similar rates of acute viral infections, the asthmatics had more severe and a greater duration of symptom scores, including lower respiratory tract symptoms, and a greater decrease in lung function [4]. This important finding was the first to suggest that there may be some inherent differences in the way that asthmatic and non-asthmatic individuals respond to respiratory viral infections, and such differences may be important in the role of viral infections in asthma. The exactly differences at the time were unknown; however, previous data had shown that asthmatic tissues often had over-exuberant inflammatory responses, largely through the increased activation of NF-kB or Rel family of transcription factors [5–7]. Wark et al. then provided a mechanistic insight into why asthmatics have a greater amount of virus-induced illness with studies involving cultured bronchial epithelial cells from adult asthmatic and non-asthmatic individuals obtained by fibre optic bronchoscopy, and infection with RV in vitro [8]. Surprisingly, asthmatic bronchial epithelial cells produced lower levels of the type I IFN-b, and also had higher levels of RV replication, assessed by both viral titration and quantitative PCR. RV induction of the pro-inflammatory cytokine IL-6, and CCL5/RANTES however were not different between the two groups strongly suggesting that the differences were specific to anti-viral IFNs, and the proinflammatory cytokine profile of these asthmatic tissues were normal. Importantly, deficient IFN-b expression was observed in both steroid-treated and steroid naı̈ve asthmatics. The asthmatic bronchial epithelial cells responded to exogenous treatment with IFN-b, exhibiting reduced RV release, neatly demonstrating that the deficiency in asthmatic cells was associated with production of anti-viral IFNb, rather than in the actions of IFN-b. Also, these pioneering studies forced a re-examination of type I IFN therapy in RV infections; type I IFN-a and IFN-b therapy which had previously been trialled in the context of the common cold, however, did not proceed further than phase two clinical trials [9, 10]. The use of IFN-b as a therapy for asthma exacerbations is therefore currently being considered. The importance of anti-viral IFNs in vivo was later elegantly shown using a human experimental infection model of adult mild-moderate asthmatics. Contoli et al. obtained bronchoalveolar lavage (BAL) cells from uninfected asthmatics and non-asthmatics [11]. Upon culturing these BAL cells (mostly macrophages) with stimuli including RV and lipopolysaccharide (LPS), BAL cells from asthmatics had lower levels of RV and LPS induced type III IFN-l, a newly described anti-viral IFN family, Correspondence: Michael R. Edwards, Department of Respiratory Medicine & Wright-Fleming Institute of Infection and Immunity, St Mary’s Campus, National Heart Lung Institute, Norfolk Place, Imperial College London, W1 2PG London, UK. E-mail: michael. edwards@imperial.ac.uk Cite this as: M. R. Edwards and S. L. Johnston, Clinical and Experimental Allergy, 2008 (38) 1416–1418. Clinical and Experimental Allergy, 38, 1416–1418 doi: 10.1111/j.1365-2222.2008.03064.x