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Despite significant advances in vaccines and antivirals, there remains a tremendous need for broadly applicable treatments that can be utilized across viral infections. Before infecting epithelial cells, viruses interact with the epithelial glycocalyx, which contains high\u2013molecular weight hyaluronan (HMWHA), a glycosaminoglycan that has beneficial effects in lung injury. In this study, we sought to determine the role of HMWHA in viral pneumonia. We infected mice with influenza or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and treated them with prophylactic or therapeutic doses of HMWHA or saline control. We performed in\u00a0vitro experiments of infection with viruses of respiratory and nonrespiratory human and animal cells and evaluated the effect of HMWHA on infection. We analyzed existing databases for expression of hyaluronan and the transcription factor E2F1. Finally, we performed a clinical trial with HMWHA in patients with severe coronavirus disease (COVID-19). Exogenously applied HMWHA improved survival in SARS-CoV-2 and influenza infection in mice by ameliorating inflammation through the inhibition of E2F1. In a clinical study, inhaled HMWHA improved outcomes in patients with severe COVID-19. Furthermore, airway epithelia naturally express HMWHA, which is induced during viral infection and prevents infection through the macromolecular crowding of viruses. Our data provide a mechanistic justification for the use of HMWHA as a broadly effective prophylactic and therapeutic agent in viral airway infection.<\/jats:p>","DOI":"10.1165\/rcmb.2025-0173oc","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T20:32:22Z","timestamp":1753734742000},"page":"52-64","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":5,"title":["Hyaluronan Ameliorates Viral Pneumonia in Mice and Humans by Inhibiting Transcription Factor E2F1"],"prefix":"10.1093","volume":"74","author":[{"given":"Vandy P","family":"Stober","sequence":"first","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences , North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol S","family":"Trempus","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health 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National Institute of Environmental Health Sciences , North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J","family":"Zaccaro","sequence":"additional","affiliation":[{"name":"DLH Corp. , LLC, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane S","family":"Der","sequence":"additional","affiliation":[{"name":"DLH Corp. , LLC, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles J","family":"Tucker","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences , North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Scappini","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences , North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Campos 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