Alternaria proteases and protease defenses in asthma

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DESCRIPTION (provided by applicant): Allergic asthma is a disease that impacts the lives of millions and is created by critical intersections of clinical, environmental, biologic, and genetic factors. Allergen exposure is essential to the development of allergic asthma, but not all allergens associate with asthma. One allergen central to the development of allergic asthma, especially in children, is Alternaria, a common mold. A critical feature of Alternaria differentiating it from more benign allergens is protease activity. The proteases in Alternaria increase its biological activity by disrupting epithelial cell tight junctions, activating epithelial cells, and increasing lung inflammation. There are endogenous inhibitors of proteases, including SERine Protease INhibitors (Serpins) and Stefin protease inhibitors. These inhibitors are strongly upregulated with Alternaria exposure. The Central Hypothesis of this application is that Alternaria proteases are essential to Alternaria acting as an asthmagen by directly targeting the epithelium but these effects are modulated by Alternaria-induced host antiproteases. We will utilize proteomics, in vitro assays, and murine models of Alternaria-induced lung inflammation to assess the interaction of the epithelium and host antiproteases with Alternaria proteases and determine their impact on the development of allergic asthma. PUBLIC HEALTH RELEVANCE: Alternaria is a protease containing allergic pathogen central to the development of allergic asthma. This application investigates the interaction of Alternaria proteases with the host protease defenses in the pathogenesis of asthma. The results may lead to both primary prevention of asthma and novel asthma treatment options.