A nonsense mutation in TLR5 is associated with survival and reduced IL-10 and TNF-α levels in human melioidosis

Background: melioidosis,caused by the flagellated bacterium burkholderia pseudomallei,is a life-threatening and increasingly recognized emerging disease. toll-like receptor (tlr) 5 is a germline-encoded pattern recognition receptor to bacterial flagellin. we evaluated the association of a nonsense tlr5 genetic variant that truncates the receptor with clinical outcomes and with immune responses in melioidosis. methodology/principal findings: we genotyped tlr5 c.1174c>t in 194 acute melioidosis patients in thailand. twenty-six (13%) were genotype ct or tt. in univariable analysis,carriage of the c.1174c>t variant was associated with lower 28-day mortality (odds ratio (or) 0.21,95% confidence interval (ci) 0.05–0.94,p = 0.04) and with lower 90-day mortality (or 0.25,95% ci 0.07–086,p = 0.03). in multivariable analysis adjusting for age,sex,diabetes and renal disease,the adjusted or for 28-day mortality in carriers of the variant was 0.24 (95% ci 0.05–1.08,p = 0.06); and the adjusted or for 90-day mortality was 0.27 (95% ci 0.08–0.97,p = 0.04). c.1174c>t was associated with a lower rate of bacteremia (p = 0.04) and reduced plasma levels of il-10 (p = 0.049) and tnf-α (p < 0.0001). we did not find an association between c.1174c>t and ifn-γ elispot (t-cell) responses (p = 0.49),indirect haemagglutination titers or igg antibodies to bacterial flagellin during acute melioidosis (p = 0.30 and 0.1,respectively). conclusions/significance: this study independently confirms the association of tlr5 c.1174c>t with protection against death in melioidosis,identifies lower bacteremia,il-10 and tnf-α production in carriers of the variant with melioidosis,but does not demonstrate an association of the variant with acute t-cell ifn-γ response,indirect haemagglutination antibody titer,or anti-flagellin igg antibodies. © 2017 chaichana et al.