A nonsense mutation in TLR5 is associated with survival and reduced IL-10 and TNF-α levels in human melioidosis.
A nonsense mutation in TLR5 is associated with survival and reduced IL-10 and TNF-α levels in human melioidosis.
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DOI：
10.1371/journal.pntd.0005587
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发表时间：
2017-05
影响因子：
3.8
通讯作者：
West TE
中科院分区：
文献类型：
--
作者：
Chaichana P;Chantratita N;Brod F;Koosakulnirand S;Jenjaroen K;Chumseng S;Sumonwiriya M;Burtnick MN;Brett PJ;Teparrukkul P;Limmathurotsakul D;Day NPJ;Dunachie SJ;West TE
类鼻疽病是由鞭毛细菌假腮腺伯克霍尔德氏菌引起的一种威胁生命的新兴疾病，越来越为人们所认识。Toll样受体(TLR5)是细菌鞭毛蛋白的种系编码模式识别受体。我们评估了一种截断TLR5受体的无意义TLR5基因变异与临床结果和类鼻疽病免疫反应的相关性。我们对194例泰国急性类鼻炎患者进行了TLR5 c.1174C>；T基因分型。26例(13%)为CT或TT基因。在单变量分析中，携带c.1174C>；T变异与较低的28天死亡率(优势比(OR)0.21，95%可信区间(CI)0.05~0.94，P=0.04)和较低的90天死亡率(OR 0.25，95%CI 0.07~086，P=0.03)相关。在调整了年龄、性别、糖尿病和肾脏疾病的多因素分析中，该变异携带者28天死亡率的调整OR为0.24(95%CI 0.05~1.08，P=0.06)，90天死亡率的调整OR为0.27(95%CI 0.08~0.97，P=0.04)。C.1174C>；T组菌血症发生率较低(P=0.04)，血浆IL-10和肿瘤坏死因子-α水平降低(P=0.049和0.0001)。我们未发现C.1174C和gt；T与干扰素-γELISPOT应答(P=0.49)、间接血凝滴度或细菌鞭毛抗体在急性类鼻疽病中的相关性(P=0.30和0.1)。这项研究独立地证实了TLR5c.1174C>；T与防止类鼻疽死亡的关联，在类鼻疽变异的携带者中发现了较低的菌血症、IL-10和肿瘤坏死因子-α的产生，但没有证明该变异与急性T细胞干扰素-γ反应、间接血凝抗体效价或抗鞭毛蛋白抗体有关。类鼻疽是东南亚和澳大利亚北部的一种高死亡率传染病，由假鼻疽伯克霍尔德氏菌引起，这种细菌是一种鞭毛、杆状革兰氏阴性细菌。了解针对类鼻疽的保护性宿主免疫反应是有效开发疫苗的基础。先前的一项研究表明，编码细菌鞭毛蛋白受体截短的TLR5终止密码子多态性与预防类鼻疽病死亡之间存在密切关系。在这项研究中，我们证实了这种基因变异与泰国东北部成人急性类鼻疽病患者的存活率之间的关系，并确定了与较低的菌血症发生率有关。我们还证明了该变异与外周血淋巴细胞计数的增加有关，但我们没有发现与假单胞菌特异性淋巴细胞反应有关，即干扰素-γ分泌T细胞反应、间接血凝滴度或抗鞭毛蛋白抗体。此外，携带TLR5变异型的患者血浆中IL-10和肿瘤坏死因子-α水平显著降低。我们的发现进一步加深了对TLR5在保护宿主免疫反应中的作用的理解，以防止致命的类鼻疽病，并为开发新型疫苗和治疗类鼻疽病的努力提供了信息。
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. 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). 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. Melioidosis is a high-mortality infectious disease in Southeast Asia and northern Australia caused by Burkholderia pseudomallei, which is a flagellated, rod-shaped Gram-negative bacterium. Understanding protective host immune responses to melioidosis is fundamental for effective vaccine development. A previous study demonstrated a strong relationship between a TLR5 stop codon polymorphism that encodes a truncated receptor for bacterial flagellin and protection against death from melioidosis. In this study, we confirmed the relationship of this genetic variant with survival from acute melioidosis in adult patients in northeast Thailand, and identified an association with a lower rate of bacteremia. We also demonstrated that this variant was associated with an increase in peripheral lymphocyte count, but we did not find an association with B. pseudomallei-specific lymphocyte responses; i.e., IFN-γ secreted T cell response, indirect haemagglutination titers or anti-flagellin IgG antibodies. In addition, patients with the TLR5 variant have significantly lower levels of IL-10 and TNF-α cytokines in plasma. Our findings further the understanding of the role of TLR5 in protective host immune responses against fatal melioidosis, and inform efforts to develop novel vaccines and therapeutics for melioidosis.