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A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to Legionnaires’ Disease

A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to Legionnaires’ Disease
Author: 
Thomas R. Hawn, MD, PhD
Published: 
Nov 2003
Publisher: 
Journal of Experimental Medicine

A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease.

TitleA common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease.
Publication TypeJournal Article
Year of Publication2003
AuthorsHawn, TR, Verbon, A, Lettinga, KD, Zhao, LPing, Li, SSue, Laws, RJ, Skerrett, SJ, Beutler, B, Schroeder, L, Nachman, A, Ozinsky, A, Smith, KD, Aderem, A
JournalJ Exp Med
Volume198
Issue10
Pagination1563-72
Date Published2003 Nov 17
ISSN0022-1007
KeywordsCodon, Terminator, Flagellin, Genetic Predisposition to Disease, Humans, Legionnaires' Disease, Membrane Glycoproteins, Polymorphism, Single Nucleotide, Receptors, Cell Surface, Signal Transduction, Toll-Like Receptor 5, Toll-Like Receptors
Abstract

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.

DOI10.1084/jem.20031220
Alternate JournalJ. Exp. Med.