A Common Dominant TLR5 Stop Codon Polymorphism Abolishes Flagellin Signaling and Is Associated with Susceptibility to Legionnaires' Disease
By T. Hawn, A. Verbon, K. Lettinga, Lue Ping Zhao, Shuying S. Li, Richard J. Laws, S. Skerrett, B. Beutler, Lea Schroeder, A. Nachman and 3 more. Journal of Experimental Medicine, 2003
663 citations recorded by the source corpus.
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.
Subfields: Endocrinology, Immunology
View Paper: https://www.semanticscholar.org/paper/36e9cbcce26432ef0038580e3294b3fd89f0aea9
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In Endocrinology
In Immunology
- T. Mogensen
- Satoshi Uematsu
- Shizuo Akira
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- Taro Kawai
- O. Takeuchi
- Daniel B. Stetson
- Zhijian J. Chen
Citations in the corpus
- Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses (2009, background): “In contrast, TLR5 has a stop codon variant (TLR5 392STOP) that is associated with increased susceptibility to pneumonia caused by L. pneumophila (117).”
- Toll-like receptors and innate immunity (2006, background): “A common stop codon polymorphism in the ligand-binding domain of TLR5 (TLR5 392STOP SNP) is unable to mediate flagellin signaling and is associated with susceptibility to pneumonia caused by Legionella pneumophila [19].”
- Pathogen recognition and innate immunity. (2006, neutral): “The TLR5392STOP mutant protein functions as a dominant-negative receptor that severely impairs TLR5-mediated signaling and is associated with susceptibility to pneumonia caused by the flagellated bacterium L. pneumophila (Hawn et al., 2003).”