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Innate Immunity in the Pathogenesis of Virus-induced Asthma Exacerbations

¹ Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and Immunity, Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom

Correspondence and requests for reprints should be addressed to Professor Sebastian L. Johnston, M.D., Ph.D., Department of Respiratory Medicine, National Heart and Lung Institute, Wright Fleming Institute of Infection and Immunity and MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, Norfolk Place, London W2 1PG, UK. E-mail: s.johnston{at}imperial.ac.uk

ABSTRACT

The major asthma morbidity, mortality, and health care costs are a result of acute exacerbations. However, exacerbations are only partially responsive to current therapies and new approaches to treatment are needed. The great majority of acute asthma exacerbations are associated with respiratory viral infections and, of viruses implicated, approximately 60% are human rhinoviruses (RVs). The mechanisms of RV-induced asthma exacerbations are poorly understood. We have previously shown that adults with asthma have increased susceptibility to naturally occurring RV infections. Our recent studies have investigated mechanisms of innate host defense against RV infection. First, primary bronchial epithelial cells from subjects with asthma were shown to replicate RV in vitro to several logs, whereas those of normal control subjects were resistant to infection. This resistance was a result of rapid induction of apoptosis and of interferon (IFN)-ß in the normal cells, whereas these responses were deficient in asthmatic cells. These studies were recently extended to a novel family of three related proteins, the IFN-s 1–3, production of which was also deficient in vitro and related to asthma exacerbation severity in vivo. These studies identify novel mechanisms for the increased susceptibility of subjects with asthma to RV infection. Further studies are now required to investigate whether administration of IFN-ß or IFN- may be beneficial in the treatment of asthma exacerbations, to determine whether similar deficiencies are observed in children and in subjects with nonatopic asthma, and to investigate the mechanisms of deficient IFN production in asthma to help identify better therapeutic strategies for asthma exacerbations.

Key Words: virus infections • asthma • innate immunity

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