Iron Induces Aspergillus Proteases in Cystic Fibrosis Allergic Bronchopulmonary Aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease triggered by inhaled Aspergillus fumigatus (Af) spores (i.e., conidia), in persons with cystic fibrosis (CF). High iron levels have been commonly described in CF respiratory secretions. Af proteases cause a severe allergic immune response, leading to pulmonary exacerbations and progressive lung function decline. The stimuli that promote Af proteases in ABPA are poorly understood. Therefore, we sought to determine if airway iron is a critical factor in CF-ABPA by regulating fungal protease production. We used transcriptomics and proteomics to investigate the role of iron in stimulating the production of Af proteases and evaluated the impact of these iron-induced Af proteases on Th2 immune response in CF bronchial epithelial (CFBE) cells and in a CF-ABPA murine model. Transcriptional analysis showed significant upregulation of Af proteases with exposure to iron and a downregulation with iron chelation. This finding was validated in secretome studies showing that Af-culture filtrates (Af-cf) from iron-exposed conidia contained significantly higher levels of 14 proteases compared to controls. Exposure to iron-primed Af-cf increased the production of Th2 promoting cytokines (IL-33, IL-25 and TSLP) in CF bronchial epithelial cells compared to the wild type cells. In vivo, inoculation of CF mice with iron-primed Af conidia led to higher levels of serum IgE and Th2 cytokines (IL-4, IL-5, IL-9, IL-13) in lung tissue. These findings suggest that airway iron is a potent stimulus for Af proteases and represents a modifiable risk factor and potential therapeutic target for CF-ABPA.