Viral infections are associated with a majority of asthma exacerbations in both children and adults. In such instances, virally-induced asthma exacerbations most often occur in the setting of underlying pulmonary allergic inflammation. Respiratory syncytial virus (RSV) infections cause a significant number of asthma exacerbations in both children and adults;however, the mechanisms by which RSV infection leads to worsening of asthma symptoms and decreased lung function are not fully defined. Our preliminary data suggests that interleukin (IL)-17A is a critical regulator of RSV-induced airway responsiveness (AR) and mucus expression. In a mouse model, we found that RSV challenge in the setting of allergic lung disease resulted in increased AR and augmented airway mucus expression, compared to mice that were not challenged with RSV during allergic inflammation. The heightened AR and mucus expression in the mice that were RSV-challenged in the presence of allergic inflammation did not correlate with the lung expression of IL-13, a cytokine that is proposed to be central regulator of AR and airway mucus expression, but instead was associated with significantly increased lung IL-17A expression. In contrast, RSV challenge in the absence of allergic lung inflammation did not result in AR, mucus expression, or detectable IL-17A levels. In this proposal, we hypothesize that IL-17A produced by the combination of allergic inflammation and RSV challenge mediates RSV-induced augmented AR and airway mucus. The long-term goals of this proposal are to: 1) fully define the role of IL-17A in the heightened AR and airway mucus expression that results when RSV challenge occurs during ongoing allergic airway inflammation, and 2) define the role of prostaglandin E2 (PGE2) produced by ongoing allergic inflammation in RSV-induced lung IL-23 expression. IL-23 is a cytokine made by dendritic cells which is critical to the expansion and maintenance of IL-17A producing T cells, now known as Th17 cells. Defining the role of IL-17A in the immunobiology of virally-mediated AR and mucus induction may result in novel targets for drug development.
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