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

Academic Article
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Overview

authors

  • Hawn, T. R.
  • Verbon, A.
  • Lettinga, K. D.
  • Zhao, L. P.
  • Li, S. S.
  • Laws, R. J.
  • Skerrett, S. J.
  • Beutler, Bruce
  • Schroeder, L.
  • Nachman, A.
  • Ozinsky, A.
  • Smith, K. D.
  • Aderem, A.

publication date

  • November 2003

journal

  • Journal of Experimental Medicine  Journal

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.

subject areas

  • Codon, 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
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Research

keywords

  • bacterial infections
  • genetic markers
  • genetic predisposition to disease
  • immunity
  • inflammation
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Identity

PubMed Central ID

  • PMC2194120

International Standard Serial Number (ISSN)

  • 0022-1007

Digital Object Identifier (DOI)

  • 10.1084/jem.20031220

PubMed ID

  • 14623910
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Additional Document Info

start page

  • 1563

end page

  • 1572

volume

  • 198

issue

  • 10

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