{"doi":"10.1165/rcmb.2025-0077oc","title":"Iron induces <i>Aspergillus</i> proteases in cystic fibrosis allergic bronchopulmonary aspergillosis","abstract":"RATIONALE: 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. OBJECTIVES: Determine if airway iron is a critical factor in CF-ABPA by regulating fungal protease production. METHODS: 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 the Th2 immune response in CF bronchial epithelial (CFBE) cells and in a CF-ABPA mouse model. MEASUREMENTS AND MAIN RESULTS: Transcriptional analysis showed a 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 CFBE 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. CONCLUSIONS: 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.","journal":"American Journal of Respiratory Cell and Molecular Biology","year":2025,"id":546996,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1400944,"name":"Aijaz Ahmad","orcid":"0000-0003-2845-0727","position":1,"is_corresponding":false},{"id":1431228,"name":"Ekroop Dhillon","orcid":null,"position":2,"is_corresponding":false},{"id":890845,"name":"Efthymia Iliana Matthaiou","orcid":"0000-0002-0907-0203","position":3,"is_corresponding":false},{"id":348400,"name":"Amer Ali Abd El‐Hafeez","orcid":"0000-0002-4822-6581","position":4,"is_corresponding":false},{"id":890846,"name":"Wayland Chiu","orcid":"0000-0001-6992-3020","position":5,"is_corresponding":false},{"id":373651,"name":"Beate Illek","orcid":"0000-0003-0076-3553","position":6,"is_corresponding":false},{"id":426015,"name":"David A. Stevens","orcid":"0000-0002-5861-5716","position":7,"is_corresponding":false},{"id":264757,"name":"Carlos Milla","orcid":"0000-0001-5515-3053","position":8,"is_corresponding":false},{"id":392502,"name":"Joe L. Hsu","orcid":"0000-0002-7050-6504","position":9,"is_corresponding":false},{"id":890848,"name":"Paulami Chatterjee","orcid":"0000-0002-2204-5459","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:53:36.567932Z","pmid":"40965296","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}