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
1] Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
Genes Immun. 2014 Mar;15(2):63-71. doi: 10.1038/gene.2013.60. Epub 2013 Nov 28.
Melioidosis is a severe infection caused by the flagellated bacterium Burkholderia pseudomallei. The nonsense polymorphism TLR51174C>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, TLR51846T>C. Carriers of TLR51846T>C had broadly impaired cytokine responses induced by flagellin. TLR51846T>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 TLR51846C-dependent nuclear factor κB activation, however, suggesting an alternative mechanism for the effect. We found that TLR51846T>C was in strong LD with TLR51174C>T. Many of the blunted cytokine responses observed and the association of TLR51846T>C with survival in melioidosis patients may be attributable to TLR51174C>T, but we could not exclude an independent effect of TLR51846T>C. These data identify novel associations for TLR51846T>C, enhance our understanding of TLR5 genetic architecture in Thais and highlight the role of TLR5 in melioidosis.
类鼻疽是由具鞭毛的细菌伯克霍尔德菌引起的严重感染。无义多态性TLR5 1174C>T与泰国类鼻疽患者病情改善相关。我们推测其他TLR5变体可能调节宿主反应并决定类鼻疽的病情转归。我们对从HapMap数据库中重新挑选的12个TLR5变体进行基因分型，并检测每个变体与健康泰国受试者全血鞭毛蛋白刺激诱导的细胞因子之间的关联。我们发现三个与非同义变体TLR5 1846T>C处于连锁不平衡（LD）状态的相关标记物的细胞因子反应减弱。TLR5 1846T>C携带者的鞭毛蛋白诱导的细胞因子反应普遍受损。TLR5 184C>T与类鼻疽患者的死亡保护相关（优势比：0.62，95%置信区间：0.42-0.93，P=0.021）。然而，我们未观察到TLR5 1846C依赖性核因子κB激活受损，提示存在另一种作用机制。我们发现TLR5 1846T>C与TLR5 1174C>T处于强LD状态。观察到的许多细胞因子反应减弱以及TLR5 1846T>C与类鼻疽患者生存的关联可能归因于TLR5 1174C>T，但我们不能排除TLR5 1846T>C的独立作用。这些数据确定了TLR5 1846T>C的新关联，增进了我们对泰国人TLR5基因结构的理解，并突出了TLR5在类鼻疽中的作用。
