Genetics and Functional Mechanisms of STAT3 Polymorphisms in Human Tuberculosis.
Genetics and Functional Mechanisms of STAT3 Polymorphisms in Human Tuberculosis.
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DOI：
10.3389/fcimb.2021.669394
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发表时间：
2021
影响因子：
5.7
通讯作者：
Shen H
中科院分区：
文献类型：
--
作者：
Wang F;Huang G;Shen L;Peng Y;Sha W;Chen ZW;Shen H
转录因子3 （STAT3）在生物平衡中起着重要作用。我们和其他人之前的研究表明STAT3在抗结核（TB）的速效先天免疫中有很大的作用。我们假设stat3 SNP下调stat3导致人类对结核病易感性的变化。为了验证这一假设，我们在结核病患者（n = 470）和HC受试者（n = 356）的病例对照研究中使用SNP扫描™技术研究了STAT3 SNP，然后使用细胞模型对它们进行了功能研究。我们发现rs1053004 TT和rs1053005 AA基因型或T-A单倍型的STAT3 3 ' -UTR snp与TB易感性或TB严重程度相关。虽然TT/AA基因型与PBMC中stat3和IL-17A的低组成表达相关，但在报告者试验中，rs1053004-rs1053005 T-A单倍型的变异stat3确实降低了stat3的表达。有趣的是，在细胞模型中，表达rs1053005 AA基因型和低组成stat3的宿主PBMC对分枝杆菌感染的快速先天免疫能力降低。最后，机制实验表明，STAT3下调广泛抑制STAT3下游抗分枝杆菌活性，包括vdr相关的CAMP途径以及IL-32、iNOS和自噬机制，导致分枝杆菌感染增强。本研究结果提示，来自TT/AA基因型/T-A单倍型的低组成stat3可下调stat3，抑制下游多种抗分枝杆菌途径/机制，从而导致高风险人群分枝杆菌感染或TB增加。
Signal transducer and activator of transcription-3 (STAT3) plays an important role in biological balance. Our and others previous studies implied that STAT3 had a great effect on fast-acting innate immunity against tuberculosis (TB). We hypothesized that stat3 SNP down-regulation of STAT3 leads to a change in susceptibility to TB in humans. To test this hypothesis, we investigated STAT3 SNPs using SNP scan™ technique in a case-control study of TB patients (n = 470) and HC subjects (n = 356), and then conducted functional studies of them using cellular models. We found that SNPs in STAT3 3`-UTR of rs1053004 TT and rs1053005 AA genotypes or T-A haplotype were associated with susceptibility to TB or TB severity. While the TT/AA genotype correlated with the low constitutive expression of stat3 and IL-17A in PBMC, the variant stat3 of rs1053004-rs1053005 T-A haplotype indeed reduced stat3 expression in reporter assays. Interestingly, host PBMC expressing the rs1053005 AA genotype and low constitutive stat3 exhibited the reduced ability to mount fast-acting innate immunity against mycobacterial infection in cellular models. Finally, mechanistic experiments showed that the STAT3 down-regulation broadly depressed STAT3 downstream anti-mycobacterial activities involving VDR-related CAMP pathway as well as IL-32, iNOS and autophagy mechanisms, leading to an enhanced mycobacterial infection. The findings of this study suggest that low constitutive stat3 derived from the TT/AA genotype/T-A haplotype acts to down-regulate STAT3, depressing multiple anti-mycobacterial pathways/mechanisms downstream, which leads to an enhanced mycobacterial infection or TB in high-risk individuals.