{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:12:13Z","timestamp":1791295933101,"version":"4.1.0"},"reference-count":50,"publisher":"Rockefeller University Press","issue":"10","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2003,11,17]]},"abstract":"<jats:p>Although Toll-like receptors (TLRs) are critical mediators of the immune response to pathogens, the influence of polymorphisms in this gene family on human susceptibility to infection is poorly understood. We demonstrated recently that TLR5 recognizes flagellin, a potent inflammatory stimulus present in the flagellar structure of many bacteria. Here, we show that a common stop codon polymorphism in the ligand-binding domain of TLR5 (TLR5392STOP) is unable to mediate flagellin signaling, acts in a dominant fashion, and is associated with susceptibility to pneumonia caused by Legionella pneumophila, a flagellated bacterium. We also show that flagellin is a principal stimulant of proinflammatory cytokine production in lung epithelial cells. Together, these observations suggest that TLR5392STOP increases human susceptibility to infection through an unusual dominant mechanism that compromises TLR5's essential role as a regulator of the lung epithelial innate immune response.<\/jats:p>","DOI":"10.1084\/jem.20031220","type":"journal-article","created":{"date-parts":[[2003,11,17]],"date-time":"2003-11-17T22:17:51Z","timestamp":1069107471000},"page":"1563-1572","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":502,"title":["A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease"],"prefix":"10.1084","volume":"198","author":[{"given":"Thomas R.","family":"Hawn","sequence":"first","affiliation":[{"name":"1University of Washington Medical Center, Seattle, WA 98195"},{"name":"2Institute for Systems Biology, Seattle, WA 98103"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelies","family":"Verbon","sequence":"additional","affiliation":[{"name":"3Department of Infectious Diseases, Academic Medical Center, 1105 AZ Amsterdam, Netherlands"},{"name":"4Division of Medical Microbiology, Academic Hospital Maastricht, 6200 MD Maastricht, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamilla D.","family":"Lettinga","sequence":"additional","affiliation":[{"name":"3Department of Infectious Diseases, Academic Medical Center, 1105 AZ Amsterdam, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lue Ping","family":"Zhao","sequence":"additional","affiliation":[{"name":"5Fred Hutchinson Cancer Research Center, Seattle, WA 98109"},{"name":"6Enodar BioLogic Corporation, Seattle, WA 98101"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuying Sue","family":"Li","sequence":"additional","affiliation":[{"name":"5Fred Hutchinson Cancer Research Center, Seattle, WA 98109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Laws","sequence":"additional","affiliation":[{"name":"5Fred Hutchinson Cancer Research Center, Seattle, WA 98109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn J.","family":"Skerrett","sequence":"additional","affiliation":[{"name":"1University of Washington Medical Center, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Beutler","sequence":"additional","affiliation":[{"name":"7The Scripps Research Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Schroeder","sequence":"additional","affiliation":[{"name":"2Institute for Systems Biology, Seattle, WA 98103"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Nachman","sequence":"additional","affiliation":[{"name":"2Institute for Systems Biology, Seattle, WA 98103"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Ozinsky","sequence":"additional","affiliation":[{"name":"2Institute for Systems Biology, Seattle, WA 98103"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly D.","family":"Smith","sequence":"additional","affiliation":[{"name":"1University of Washington Medical Center, Seattle, WA 98195"},{"name":"2Institute for Systems Biology, Seattle, WA 98103"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Aderem","sequence":"additional","affiliation":[{"name":"2Institute for Systems Biology, Seattle, WA 98103"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2003,11,17]]},"reference":[{"key":"2023072512001477900_BIB1","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1056\/NEJM199512143332408","volume":"333","year":"1995","journal-title":"N. 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