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

486 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Hawn, T. R., Verbon, A., Lettinga, K. D., Zhao, L. P., Li, S. S., Laws, R. J., Skerrett, S. J., Beutler, B., Schroeder, L., Nachman, A., Ozinsky, A., Smith, K. D., & 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, 198(10), 1563-1572. https://doi.org/10.1084/jem.20031220