The molecular basis of impaired innate immunity to virus infection in asthma

We are investigating the reasons why common cold viruses make asthma symptoms worse. These periods of worsened symptoms (exacerbations) can be severe enough to cause an increase in the need for medications, and may result in hospitalisation and even death. The most common trigger for these serious exacerbations is a virus infection, such as the common cold. Recently, we have made progress in addressing this problem by demonstrating that the cells that line the airways (epithelial cells) which are the primary target for infection by the common cold virus fail to mount an effective anti-viral response if they are derived from an asthmatic donor. This means that cold viruses are able to replicate more efficiently resulting in lingering lower respiratory tract problems. The purpose of our study is to investigate this defect with a view to identifying novel targets for development of new and effective therapies for virus-induced exacerbations of asthma where there is an unmet clinical need. We also propose to examine the anti-viral response of cells from wheezy and asthmatic children because a defective response in early life may explain the link between viral infections and the onset of asthma.

Epidemiological studies have linked viral respiratory infection in early life to asthma pathogenesis. Furthermore, the majority of acute asthma exacerbations, especially in children, follow upper respiratory viral infections, of which at least 60% are caused by human rhinoviruses (RV). Despite the increasing frequency of asthma and the associated morbidity, the mechanisms by which RVs may trigger or exacerbate asthma are incompletely understood. Recent studies at the University of Southampton have shown that bronchial epithelial cells (BECs) from asthmatic donors have a defective innate immune response characterized by reduced interferon beta (IFNb) production and reduced apoptosis following infection with RV. These studies provide, for the first time, an explanation for the tendency of asthmatic subjects to have lingering lower respiratory tract problems as a consequence of RV infection.
Recognizing that exacerbations of asthma represent the most severe aspect of this disease and account for a substantial proportion of the health costs both in children and adults, the purpose of the proposed investigation is to test the hypothesis that the impaired innate anti-viral immune response in epithelial cells from asthmatic subjects is a specific defect involving signalling pathways that recognize viral RNA resulting in failure to activate transcription from the IFNb promoter; we further postulate that this defect is an intrinsic or acquired defect that increases the susceptibility of asthmatic children to RV infection.
To test our hypotheses, we will investigate:
a) the immediate response to virus infection by focussing on activation of pathways that recognize dsRNA (TLR3, RIG-1 and PKR) leading to IRF3 activation and transcription of IFNb;
b) the ability of asthmatic epithelial cells to amplify the immediate innate immune response by analyzing autocrine/paracrine stimulation of the type 1 interferon receptor leading to STAT1 activation and transcription of IRF3 and IRF7 leading to sustained expression of type 1 interferons;
c) the potential of compounds that modulate interferon production to protect asthmatic epithelial cells against RV infection;
d) the susceptibility of bronchial epithelial cells from asthmatic children to RV infection in vitro.

These studies have the potential to identify novel targets for development of new and effective therapies for virus-induced exacerbations of asthma where there is an unmet clinical need. Demonstration of a defective innate immune response in asthmatic or wheezy children, will have implications both for treatment of virally-induced exacerbation of asthma in children, and for disease pathogenesis which is strongly associated with respiratory virus infection in early life.