Chaichana Panjaporn, Chantratita Narisara, Brod Florian, Koosakulnirand Sirikamon, Jenjaroen Kemajittra, Chumseng Suchintana, Sumonwiriya Manutsanun, Burtnick Mary N, Brett Paul J, Teparrukkul Prapit, Limmathurotsakul Direk, Day Nicholas P J, Dunachie Susanna J, West T Eoin
Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.
Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
PLoS Negl Trop Dis. 2017 May 5;11(5):e0005587. doi: 10.1371/journal.pntd.0005587. eCollection 2017 May.
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.
类鼻疽病由具鞭毛的细菌伪鼻疽伯克霍尔德菌引起，是一种危及生命且日益受到认可的新发疾病。Toll样受体（TLR）5是一种种系编码的针对细菌鞭毛蛋白的模式识别受体。我们评估了一种导致受体截短的无义TLR5基因变异与类鼻疽病临床结局及免疫反应之间的关联。
方法/主要发现：我们对泰国194例急性类鼻疽病患者的TLR5基因c.1174C>T进行了基因分型。26例（13%）为CT或TT基因型。在单变量分析中，c.1174C>T变异的携带者28天死亡率较低（比值比（OR）0.21，95%置信区间（CI）0.05 - 0.94，P = 0.04），90天死亡率也较低（OR 0.25，95% CI 0.07 - 0.86，P = 0.03）。在对年龄、性别、糖尿病和肾病进行校正的多变量分析中,变异携带者28天死亡率的校正OR为0.24（95% CI 0.05 - 1.08，P = 0.06）；90天死亡率的校正OR为0.27（95% CI 0.08 - 0.97，P = 0.04）。c.1174C>T与菌血症发生率较低（P = 0.04）以及血浆中白细胞介素 - 10（P = 0.049）和肿瘤坏死因子 - α水平降低（P < 0.0001）相关。我们未发现c.1174C>T与急性类鼻疽病期间的IFN - γ ELISPOT（T细胞）反应（P = 0.49）、间接血凝滴度或针对细菌鞭毛蛋白的IgG抗体之间存在关联（分别为P = 0.30和0.1）。
结论/意义：本研究独立证实了TLR5基因c.1174C>T与类鼻疽病死亡保护之间的关联，确定了该变异携带者在类鼻疽病中菌血症、IL - 10和TNF - α产生较低，但未证明该变异与急性T细胞IFN - γ反应、间接血凝抗体滴度或抗鞭毛蛋白IgG抗体之间存在关联。
