Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis

• Published in: Genes and immunity Vol. 15; no. 2; pp. 63 - 71
• Main Authors: Chantratita, N, Tandhavanant, S, Myers, N D, Chierakul, W, Robertson, J D, Mahavanakul, W, Singhasivanon, P, Emond, M J, Peacock, S J, West, T E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2014; Nature Publishing Group
• Subjects: 631/208/726/649; 631/250/262; 692/699/255/1318; Adult; Bacteria; Biomedical and Life Sciences; Biomedicine; Burkholderia pseudomallei; Burkholderia pseudomallei - immunology; Cancer Research; Cell Line; Cytokines; Cytokines - blood; Diagnosis; Female; Flagellin; Flagellin - immunology; Gene Expression; Genes; Genetic aspects; Genetic variation; Genotype; Gram-negative bacteria; Gram-positive bacteria; HEK293 Cells; Human Genetics; Humans; Immunity, Innate; Immunology; Infections; Linkage Disequilibrium; Male; Medicine; Melioidosis; Melioidosis - blood; Melioidosis - immunology; Melioidosis - mortality; NF-kappa B - blood; original-article; Pathogens; Patient outcomes; Physiological aspects; Polymorphism; Polymorphism, Single Nucleotide; Proteins; Pseudomonas infections; Salmonella typhimurium - immunology; Signal Transduction - genetics; Signal Transduction - immunology; TLR5 protein; Toll-Like Receptor 5 - blood; Toll-Like Receptor 5 - genetics; Toll-Like Receptor 5 - immunology; Toll-like receptors; Treatment Outcome; Young Adult; Thailand; United States > US; Bangkok Thailand; genetic variation; melioidosis; flagellin; TLR5; innate immune response
• ISSN: 1466-4879; 1476-5470; 1476-5470
• DOI: 10.1038/gene.2013.60

Melioidosis is a severe infection caused by the flagellated bacterium Burkholderia pseudomallei . The nonsense polymorphism TLR5 1174C>T is associated with improved outcome in Thais with melioidosis. We hypothesized that other TLR5 variants may modulate the host response and determine outcome in melioidosis. We genotyped 12 TLR5 variants selected de novo from the HapMap database and examined the association of each with cytokines induced by flagellin stimulation of whole blood from healthy Thai subjects. We found a blunted cytokine response for three related markers that were in linkage disequilibrium (LD) with a non-synonymous variant, TLR5 1846T>C . Carriers of TLR5 1846T>C had broadly impaired cytokine responses induced by flagellin. TLR5 1846T>C was associated with protection against death in melioidosis patients (odds ratio: 0.62, 95% confidence interval: 0.42–0.93, P= 0.021). We observed no impairment in TLR5 1846C -dependent nuclear factor κB activation, however, suggesting an alternative mechanism for the effect. We found that TLR5 1846T>C was in strong LD with TLR5 1174C>T . Many of the blunted cytokine responses observed and the association of TLR5 1846T>C with survival in melioidosis patients may be attributable to TLR5 1174C>T , but we could not exclude an independent effect of TLR5 1846T>C. These data identify novel associations for TLR5 1846T>C , enhance our understanding of TLR5 genetic architecture in Thais and highlight the role of TLR5 in melioidosis.