The Journal of Experimental Medicine
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Published 17 November 2003. doi:10.1084/jem.20031220
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© Rockefeller University Press, 0022-1007/2003/11/1563 $5.00
The Journal of Experimental Medicine, Volume 198, Number 10, 1563-1572

A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease

Thomas R. Hawn1,2, Annelies Verbon3,4, Kamilla D. Lettinga3, Lue Ping Zhao5,6, Shuying Sue Li5, Richard J. Laws5, Shawn J. Skerrett1, Bruce Beutler7, Lea Schroeder2, Alex Nachman2, Adrian Ozinsky2, Kelly D. Smith1,2 and Alan Aderem2

1 University of Washington Medical Center, Seattle, WA 98195
2 Institute for Systems Biology, Seattle, WA 98103
3 Department of Infectious Diseases, Academic Medical Center, 1105 AZ Amsterdam, Netherlands
4 Division of Medical Microbiology, Academic Hospital Maastricht, 6200 MD Maastricht, Netherlands
5 Fred Hutchinson Cancer Research Center, Seattle, WA 98109
6 Enodar BioLogic Corporation, Seattle, WA 98101
7 The Scripps Research Institute, La Jolla, CA 92037

Address correspondence to Thomas R. Hawn, Institute for Systems Biology, 1441 N. 34th St., Seattle, WA 98103. Phone: (206) 732-1377; Fax: (413) 691-8922; email: thawn{at}u.washington.edu

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.

Key Words: inflammation • immunity • genetic predisposition to disease • genetic markers • bacterial infections


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