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

Thomas R. Hawn, Annelies Verbon, Kamilla D. Lettinga, Lue Ping Zhao, Shuying Sue Li, Richard J. Laws, Shawn J. Skerrett, Bruce Beutler, Lea Schroeder, Alex Nachman, Adrian Ozinsky, Kelly D. Smith, Alan Aderem

Research output: Contribution to journalArticle

481 Citations (Scopus)

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 (TLR5 392STOP) 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.

Original languageEnglish (US)
Pages (from-to)1563-1572
Number of pages10
JournalJournal of Experimental Medicine
Volume198
Issue number10
DOIs
StatePublished - Nov 17 2003

Fingerprint

Legionnaires' Disease
Flagellin
Terminator Codon
Bacteria
Legionella pneumophila
Lung
Toll-Like Receptors
Infection
Innate Immunity
Pneumonia
Epithelial Cells
Cytokines
Ligands
Genes

Keywords

  • Bacterial infections
  • Genetic markers
  • Genetic predisposition to disease
  • Immunity
  • Inflammation

ASJC Scopus subject areas

  • Immunology

Cite this

A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease. / Hawn, Thomas R.; Verbon, Annelies; Lettinga, Kamilla D.; Zhao, Lue Ping; Li, Shuying Sue; Laws, Richard J.; Skerrett, Shawn J.; Beutler, Bruce; Schroeder, Lea; Nachman, Alex; Ozinsky, Adrian; Smith, Kelly D.; Aderem, Alan.

In: Journal of Experimental Medicine, Vol. 198, No. 10, 17.11.2003, p. 1563-1572.

Research output: Contribution to journalArticle

Hawn, TR, Verbon, A, Lettinga, KD, Zhao, LP, Li, SS, Laws, RJ, Skerrett, SJ, Beutler, B, Schroeder, L, Nachman, A, Ozinsky, A, Smith, KD & Aderem, A 2003, 'A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease', Journal of Experimental Medicine, vol. 198, no. 10, pp. 1563-1572. https://doi.org/10.1084/jem.20031220
Hawn, Thomas R. ; Verbon, Annelies ; Lettinga, Kamilla D. ; Zhao, Lue Ping ; Li, Shuying Sue ; Laws, Richard J. ; Skerrett, Shawn J. ; Beutler, Bruce ; Schroeder, Lea ; Nachman, Alex ; Ozinsky, Adrian ; Smith, Kelly D. ; Aderem, Alan. / A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease. In: Journal of Experimental Medicine. 2003 ; Vol. 198, No. 10. pp. 1563-1572.
@article{8cd558bbe0954873b35486ed61848ac7,
title = "A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease",
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 (TLR5 392STOP) 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.",
keywords = "Bacterial infections, Genetic markers, Genetic predisposition to disease, Immunity, Inflammation",
author = "Hawn, {Thomas R.} and Annelies Verbon and Lettinga, {Kamilla D.} and Zhao, {Lue Ping} and Li, {Shuying Sue} and Laws, {Richard J.} and Skerrett, {Shawn J.} and Bruce Beutler and Lea Schroeder and Alex Nachman and Adrian Ozinsky and Smith, {Kelly D.} and Alan Aderem",
year = "2003",
month = "11",
day = "17",
doi = "10.1084/jem.20031220",
language = "English (US)",
volume = "198",
pages = "1563--1572",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "10",

}

TY - JOUR

T1 - A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease

AU - Hawn, Thomas R.

AU - Verbon, Annelies

AU - Lettinga, Kamilla D.

AU - Zhao, Lue Ping

AU - Li, Shuying Sue

AU - Laws, Richard J.

AU - Skerrett, Shawn J.

AU - Beutler, Bruce

AU - Schroeder, Lea

AU - Nachman, Alex

AU - Ozinsky, Adrian

AU - Smith, Kelly D.

AU - Aderem, Alan

PY - 2003/11/17

Y1 - 2003/11/17

N2 - 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 (TLR5 392STOP) 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.

AB - 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 (TLR5 392STOP) 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.

KW - Bacterial infections

KW - Genetic markers

KW - Genetic predisposition to disease

KW - Immunity

KW - Inflammation

UR - http://www.scopus.com/inward/record.url?scp=10744226016&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10744226016&partnerID=8YFLogxK

U2 - 10.1084/jem.20031220

DO - 10.1084/jem.20031220

M3 - Article

VL - 198

SP - 1563

EP - 1572

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 10

ER -