A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease.
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.
Hawn
Thomas R
TR
Institute for Systems Biology, 1441 N. 34th St., Seattle, WA 98103, USA. thawn@u.washington.edu
Verbon
Annelies
A
Lettinga
Kamilla D
KD
Zhao
Lue Ping
LP
Li
Shuying Sue
SS
Laws
Richard J
RJ
Skerrett
Shawn J
SJ
Beutler
Bruce
B
Schroeder
Lea
L
Nachman
Alex
A
Ozinsky
Adrian
A
Smith
Kelly D
KD
Aderem
Alan
A
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
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