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 (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.
authors: Institute for Systems Biology, 1441 N. 34th St., Seattle, WA 98103, USA. thawn@u.washington.edu
authors: Thomas R
authors: TR
authors: Hawn
authors: Annelies
authors: A
authors: Verbon
authors: Kamilla D
authors: KD
authors: Lettinga
authors: Lue Ping
authors: LP
authors: Zhao
authors: Shuying Sue
authors: SS
authors: Li
authors: Richard J
authors: RJ
authors: Laws
authors: Shawn J
authors: SJ
authors: Skerrett
authors: Bruce
authors: B
authors: Beutler
authors: Lea
authors: L
authors: Schroeder
authors: Alex
authors: A
authors: Nachman
authors: Adrian
authors: A
authors: Ozinsky
authors: Kelly D
authors: KD
authors: Smith
authors: Alan
authors: A
authors: Aderem
mesh_terms: D018388:Codon, Terminator; D005408:Flagellin / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007877:Legionnaires' Disease / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors
chemical_list: D018388:Codon, Terminator; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D051193:Toll-Like Receptors; D005408:Flagellin