Rhinoviruses are the most common cause of virally-induced asthma exacerbations which continue to account for the greatest burden in terms of morbidity, mortality and cost associated with this disease. IL-25 activates type-2-driven inflammation and is potentially important in virally-induced asthma exacerbations. Rhinovirus-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental rhinovirus infection. In mice rhinovirus infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbationspecific responses including type-2 cytokine expression, mucus production and recruitment of eosinophils, neutrophils, basophils, T and non-T type-2 cells. We have identified that asthmatic epithelial cells possess increased intrinsic capacity for expression of a pro-type-2 cytokine in

Rhinoviruses are the most common virus to infect man causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity however their function during rhinovirus infection in vivo is undefined. In RV infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expression of IL-15 and IL-15Rα which in turn were required for NK- and CD8+ T-cell responses. Treatment with IL-15-IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9 and CXCL10 followed by recruitment of activated, IFN-γ expressing NK, CD8+ and CD4+ T cells. Treating infected IFNAR1−/− mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ and CXCL9 (but not CXCL10) expression also followed by NK-, CD8+- and CD4+-T cell recruitment and activation. We have demonstrated that type I IFN induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.