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Although the proinflammatory roles of SA-SAgs is well-established, their role in the immunopathogenesis of CF lung disease is unexplored. Herein, we demonstrate that 60-80% of pediatric and adult CF SA isolates carried at least one SA-SAg gene, with the former harboring potent SA-SAgs (Staphylococcal enterotoxin A and B) more frequently (30-60%). Biofilms of clinical SA isolates readily produced biologically active SA-SAgs in artificial sputum medium and purified SA-SAgs retained their bioactivity in human CF sputum in vitro. Repeated intratracheal challenge with purified SA-SAgs induced a robust pulmonary inflammatory response in CF mouse models (\u03b2ENAC and CFGC transgenic mice) expressing HLA-DR3 in a dose-dependent manner, with the low dose favoring a type 2 eosinophilic lung inflammatory response, and a high dose eliciting a type 1 inflammatory response with neutrophilic lung inflammation and higher mortality. In vivo neutralization of IFN-\u03b3 also promoted SA-SAg-driven type 2 inflammation. Intratracheal infection with sub-lethal dose of a clinical SA isolate producing SEB, but not the SEB-deficient mutant isogenic SA strain, also elicited an eosinophilic inflammatory response.<\/jats:p>","DOI":"10.1101\/2025.05.07.652658","type":"posted-content","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:15:11Z","timestamp":1747095311000},"source":"Crossref","is-referenced-by-count":0,"title":["Prevalence, Production and the Role of\n                  <i>Staphylococcus aureus<\/i>\n                  Superantigens in Cystic Fibrosis Lung Disease"],"prefix":"10.64898","author":[{"given":"Ying","family":"Sun","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Buqu","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sahil","family":"Chhabra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jade","family":"Tolentino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesse","family":"Natarajan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zachary","family":"Harris","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail","family":"Stanley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colleen","family":"Bianco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Planet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shardulendra P.","family":"Sherchand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajan","family":"Adhikari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javad","family":"Aman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuchen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon","family":"Koff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Govindarajan","family":"Rajagopalan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"10290","key":"2025051412252037000_2025.05.07.652658v1.1","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1016\/S0140-6736(20)32542-3","article-title":"Cystic fibrosis","volume":"397","year":"2021","journal-title":"The Lancet"},{"key":"2025051412252037000_2025.05.07.652658v1.2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.15.2.194-222.2002"},{"key":"2025051412252037000_2025.05.07.652658v1.3","doi-asserted-by":"crossref","unstructured":"Cohen-Cymberknoh, M. , Infection and Inflammation in the Cystic fibrosis (CF) airway. 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