TLR5 as an anti-inflammatory target and modifier gene in cystic fibrosis.
New treatments are needed to improve the health of people with cystic fibrosis (CF). Reducing lung-damaging inflammation is likely to be beneficial, but specific anti-inflammatory targets have not been identified. By combining cellular immunology with a population-based genetic modifier study, we examined TLR5 as an anti-inflammatory target and modifier gene in CF. Using two pairs of human CF and control airway epithelial cells, we demonstrated that the TLR5-flagellin interaction is a major mediator of inflammation following exposure to Pseudomonas aeruginosa. To validate TLR5 as an anti-inflammatory target, we analyzed the disease modifying effects of the TLR5 c.1174C>T single nucleotide polymorphism (rs5744168) in a large cohort of CF patients (n = 2219). rs5744168 encodes a premature stop codon and the T allele is associated with a 45.5-76.3% reduction in flagellin responsiveness (p < 0.0001). To test the hypothesis that reduced TLR5 responsiveness would be associated with improved health in CF patients, we examined the relationship between rs5744168 and two clinical phenotypes: lung function and body weight. Adults with CF carrying the TLR5 premature stop codon (CT or TT genotype) had a higher body mass index than did CF patients homozygous for the fully functional allele (CC genotype) (p = 0.044); however, similar improvements in lung function associated with the T allele were not statistically significant. Although follow-up studies are needed to confirm the impact of TLR5 on nutritional status, this translational research provides evidence that genetic variation in TLR5 resulting in reduced flagellin responsiveness is associated with improved health indicators in adults with CF.
Department of Paediatrics, BC Children's Hospital and Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Christoph J
CJ
Blohmke
Julie
J
Park
Aaron F
AF
Hirschfeld
Rachel E
RE
Victor
Julia
J
Schneiderman
Dorota
D
Stefanowicz
Mark A
MA
Chilvers
Peter R
PR
Durie
Mary
M
Corey
Julian
J
Zielenski
Ruslan
R
Dorfman
Andrew J
AJ
Sandford
Denise
D
Daley
Stuart E
SE
Turvey
D000328:Adult; D000483:Alleles; D015992:Body Mass Index; D002461:Cell Line, Transformed; D002648:Child; D002675:Child, Preschool; D018388:Codon, Terminator; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D005408:Flagellin / Q000276:immunology / Q000494:pharmacology; D006720:Homozygote; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D009752:Nutritional Status; D020641:Polymorphism, Single Nucleotide; D011550:Pseudomonas aeruginosa / Q000276:immunology; D012129:Respiratory Function Tests; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D018388:Codon, Terminator; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin