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In this study, we have investigated the role of IFN-\u03b3 in lethal lung inflammation using a mouse model of postinfluenza methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. To mimic the clinical scenario, animals were treated with antibiotics for effective bacterial control following MRSA superinfection. However, antibiotic therapy alone is not sufficient to improve survival of wild-type animals in this lethal acute respiratory distress syndrome model. In contrast, antibiotics induce effective protection in mice deficient in IFN-\u03b3 response. Mechanistically, we show that rather than inhibiting bacterial clearance, IFN-\u03b3 promotes proinflammatory cytokine response to cause lethal lung damage. Neutralization of IFN-\u03b3 after influenza prevents hyperproduction of TNF-\u03b1, and thereby protects against inflammatory lung damage and animal mortality. Taken together, the current study demonstrates that influenza-induced IFN-\u03b3 drives a stepwise propagation of inflammatory cytokine response, which ultimately results in fatal lung damage during secondary MRSA pneumonia, despite of antibiotic therapy.<\/jats:p>","DOI":"10.4049\/jimmunol.2100328","type":"journal-article","created":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T18:00:15Z","timestamp":1628704815000},"page":"1371-1376","source":"Crossref","is-referenced-by-count":38,"title":["IFN-\u03b3 Drives TNF-\u03b1 Hyperproduction and Lethal Lung Inflammation during Antibiotic Treatment of Postinfluenza <i>Staphylococcus aureus<\/i> Pneumonia"],"prefix":"10.1093","volume":"207","author":[{"given":"Atul K","family":"Verma","sequence":"first","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5652-9582","authenticated-orcid":false,"given":"Christopher","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3990-0343","authenticated-orcid":false,"given":"Sunil","family":"Palani","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE"},{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch , Galveston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8000-9907","authenticated-orcid":false,"given":"Dennis W","family":"Metzger","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbial Disease, Albany Medical College , Albany, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keer","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center , Omaha, NE"},{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch , Galveston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,1]]},"reference":[{"key":"2025022610320852500_r1","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1007\/s00508-020-01759-x","article-title":"A retrospective comparison between influenza and COVID-19-associated ARDS in a Croatian tertiary care center","volume":"133","author":"Gjurasin","year":"2020","journal-title":"Wien Klin Wochenschr."},{"key":"2025022610320852500_r2","doi-asserted-by":"crossref","first-page":"e00074-20","DOI":"10.1128\/CMR.00074-20","article-title":"Immunopathogenesis of coronavirus-induced acute respiratory distress syndrome (ARDS): potential infection-associated hemophagocytic lymphohistiocytosis","volume":"34","author":"Quan","year":"2020","journal-title":"Clin. 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