Defining the importance of IL-25 in rhinovirus-induced asthma exacerbations

Asthma is the most common respiratory disease and has increased over recent decades, such that in many European countries ~30% of children now report wheeze in the last year. Rhinovirus (RV) infection is the dominant individual cause of acute exacerbations in both adults and children. Despite the enormous associated illness current therapies are ineffective and the mechanisms of RV induced asthma exacerbations are poorly understood. Asthmatics produce a molecule in their lungs, IL-25, that is potentially important in causing exacerbations. We aim to understand the role of IL-25 in immune responses to RV infections and asthma exacerbations and determine if this molecule is a suitable candidate for development of better treatments. To determine if IL-25 is associated with immune responses that regulate exacerbation severity we have developed a human experimental RV-induced asthma exacerbation model. Clinical samples from this study will enable us to investigate the association between IL-25 expression and host responses that cause asthma exacerbations. To support human studies we have recently developed the world?s first mouse models of rhinovirus infection and exacerbation of asthma demonstrating numerous asthma related outcomes exacerbated by infection in the mouse. These mouse models of rhinovirus infection and asthma exacerbation will enable investigation within the mammalian airway to establish a causal role in disease for IL-25. The objective of this proposal is therefore to utilize human and models of rhinovirus-induced asthma exacerbation to define a role for IL-25 in the immune response and airways disease, research fundamental to the development of better treatments for asthma exacerbations.

We hypothesise that rhinovirus infection induces IL-25, which in atopic asthmatics, amplifies Th2 responses in the airways causing asthma exacerbations. To test this hypothesis we will employ two state of the art in vivo models. First a human model of experimental rhinovirus infection in atopic asthma and healthy subjects. This will enable us to assess RV-induced IL-25 expression during asthma exacerbations and also to compare production in asthma and healthy subjects. Furthermore we will be able correlate IL-25 production with Th2 responses, mucus production, clinical illness severity and virus load. IL-25 protein will be measured in airway lining fluid by MSD and in bronchial biopsies by immunohistochemistry. IL-25 gene expression analysis of bronchial epithelial cells taken during bronchoscopy will also be undertaken. This study will be the first to assess the role of IL-25 in asthma exacerbations and be an important addition to the few published human studies. We also plan to use mouse models of RV infection and asthma exacerbation in which we can manipulate IL-25 activity and monitor Th2 immune responses and asthma-relevant markers of airways disease. Initially we will study rhinovirus infection (minor and major group) and IL-25 expression (gene and protein) in the lung using mouse infection models previously developed by us. Next we will use a model of rhinovirus induced exacerbation of allergic airways inflammation also previously developed by us. This will enable us to investigate the effect of RV infection and allergen challenge on IL-25 expression. Using a neutralising mAb we will determine the role of IL-25 in mediating AHR, Th2 immunity and airways disease in the exacerbation of allergic airways disease model. Administering the IL-25 neutralising mAb to an IL-13- reporter mouse will enable evaluation of the role of IL-25 on IL-13 expression. If IL-25 expression is induced and related to disease outcomes in the human model, AND causally related to Th2 mediated disease outcomes in the mouse in vivo model this cytokine will be a good target to direct development of novel treatments for RV-induced asthma exacerbations.