The role of TLR9 polymorphism in susceptibility to pulmonary tuberculosis
The role of TLR9 polymorphism in susceptibility to pulmonary tuberculosis
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DOI：
10.1007/s00251-014-0806-1
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发表时间：
2014-12-01
期刊：
影响因子：
3.2
通讯作者：
Kumar, Himanshu
中科院分区：
文献类型：
--
作者：
Bharti, Deepak;Kumar, Ashish;Kumar, Himanshu
结核分枝杆菌（MTB）是肺结核（PTB）的病原体，肺结核是一个主要的健康问题，每年导致150万人死亡。宿主遗传因素通过改变针对MTB的免疫在疾病抗性/易感性中起重要作用。已知Toll样受体（TLR）传感器如TLR 2、TLR 4、TLR 8和TLR 9通过调节传感器表达和/或效应子应答在PTB中起关键作用。TLR 9启动子的单核苷酸多态性（SNP）rs 187084（T-1486 C）与各种自身免疫性疾病和癌症相关。最近的生物信息学分析预测T-1486 C SNP参与PTB，尽管其潜在作用尚不清楚。为了研究T-1486 C在PTB中的作用，我们用H37 Rv全细胞裂解物刺激PBMC。我们发现，“C”等位基因的存在增加了TLR 9的转录活性，这反过来又诱导高水平的干扰素γ诱导蛋白10（IP-10），这是PTB的生物标志物。然而，与“T”等位基因相比，观察到“C”等位基因的保护性细胞因子如IFN γ和TNF α的表达显著较少。我们进一步选择了三个不同的部落人口显示不同的易感性PTB和TLR 9启动子进行基因型分析。我们发现一个显着较低的次要等位基因频率（MAF）的T-1486 C在Baiga部落，其中较少的PTB病例报告，比在Gond和Korku部落。总的来说，这些数据表明，在rs 187084位点的次要“C”等位基因可能与PTB的易感性，这可能解释了相对较低的PTB率观察到的Baiga部落成员。
Mycobacterium tuberculosis (MTB) is the causative agent of pulmonary tuberculosis (PTB), a major health problem that leads to 1.5 million deaths annually. Host genetic factors play a significant role in disease resistance/susceptibility by altering immunity against MTB. Toll-like receptor (TLR) sensors such as TLR2, TLR4, TLR8, and TLR9 are known to play a pivotal role in PTB via modulating sensor expression and/or effector responses. Single-nucleotide polymorphism (SNP) rs187084 (T-1486C) of the TLR9 promoter is associated with various autoimmune disorders and cancers. A recent bioinformatic analysis predicted that the T-1486C SNP is involved in PTB, although its potential role is unclear. To investigate the role of T-1486C in PTB, we stimulated PBMCs with the H37Rv whole cell lysate. We found that the presence of the "C" allele increases the transcriptional activity of the TLR9, which in turn induces high levels of Interferon gamma-induced protein 10 (IP-10), a biomarker for PTB. However, the expression of protective cytokines such as IFN gamma and TNF alpha was observed significantly less with "C" allele in comparison to "T" allele. We further selected three different tribe populations showing differential susceptibility to PTB and performed genotypic analyses for the TLR9 promoter. We found a significantly lower minor allele frequency (MAF) of T-1486C in the Baiga tribe, wherein fewer PTB cases were reported, than that in the Gond and Korku tribes. Collectively, these data suggest that the minor "C" allele at rs187084 locus may be associated with susceptibility to PTB, which may explain the relatively lower PTB rates observed in Baiga tribe members.