Human genetic diversity regulating the TLR10/TLR1/TLR6 locus confers increased cytokines in response to Chlamydia trachomatis.
Human genetic diversity regulating the TLR10/TLR1/TLR6 locus confers increased cytokines in response to Chlamydia trachomatis.
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DOI：
10.1016/j.xhgg.2021.100071
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发表时间：
2022-01-13
期刊：
影响因子：
--
通讯作者：
Ko DC
中科院分区：
文献类型：
--
作者：
Barnes AB;Keener RM;Schott BH;Wang L;Valdivia RH;Ko DC
人类遗传多样性在接触传染性病原体后会对健康结果产生深远影响。对于沙眼衣原体（C. trachomatis）感染，广泛的生殖器和眼部疾病表现可能受到调节沙眼衣原体和宿主细胞之间相互作用的人类遗传差异的影响。我们利用细胞应答的多样性来证明Toll样受体1（TLR 1）、TLR 6和TLR 10位点的变异对沙眼衣原体应答中细胞因子产生的重要性。我们确定，位于与TLR 6启动子形成环的区域的单核苷酸多态性（SNP）（rs 1057807）与TLR 1、TLR 6和TLR 10的表达增加以及10种沙眼衣原体诱导的细胞因子的分泌水平相关。基于使用抑制剂、阻断抗体、RNAi和蛋白质过表达的实验，这些沙眼衣原体诱导的细胞因子的产生主要依赖于MyD 88和TLR 6。群体遗传学分析进一步表明，来自两个欧洲群体的细胞的平均IL-6反应高于来自三个非洲群体的细胞的平均反应，并且这种差异部分归因于rs 1057807等位基因频率的变化。相比之下，与不同促炎细胞因子相关的SNP（与趋化因子CXCL 10相关的rs 2869462）表现出相反的反应，强调了不同遗传变异如何促进个体免疫反应的复杂性。这项多学科的研究已经确定了一种调节TLR 6的长距离染色质相互作用和遗传变异，以扩大我们对人类遗传变异如何影响沙眼衣原体诱导的免疫反应的理解。衣原体感染有不同的结果，这些变化的原因知之甚少。在这里，我们利用细胞全基因组关联方法来表征TLR 10/TLR 1/TLR 6区域附近的一个位点，该位点与衣原体诱导的细胞因子水平相关，与TLR 6启动子相互作用，并导致人群之间的差异。
Human genetic diversity can have profound effects on health outcomes upon exposure to infectious agents. For infections with Chlamydia trachomatis (C. trachomatis), the wide range of genital and ocular disease manifestations are likely influenced by human genetic differences that regulate interactions between C. trachomatis and host cells. We leveraged this diversity in cellular responses to demonstrate the importance of variation at the Toll-like receptor 1 (TLR1), TLR6, and TLR10 locus to cytokine production in response to C. trachomatis. We determined that a single-nucleotide polymorphism (SNP) (rs1057807), located in a region that forms a loop with the TLR6 promoter, is associated with increased expression of TLR1, TLR6, and TLR10 and secreted levels of ten C. trachomatis-induced cytokines. Production of these C. trachomatis-induced cytokines is primarily dependent on MyD88 and TLR6 based on experiments using inhibitors, blocking antibodies, RNAi, and protein overexpression. Population genetic analyses further demonstrated that the mean IL-6 response of cells from two European populations were higher than the mean response of cells from three African populations and that this difference was partially attributable to variation in rs1057807 allele frequency. In contrast, a SNP associated with a different pro-inflammatory cytokine (rs2869462 associated with the chemokine CXCL10) exhibited an opposite response, underscoring the complexity of how different genetic variants contribute to an individual’s immune response. This multidisciplinary study has identified a long-range chromatin interaction and genetic variation that regulates TLR6 to broaden our understanding of how human genetic variation affects the C. trachomatis-induced immune response. Chlamydia infections have diverse outcomes, and the causes of these variations are poorly understood. Here, we leverage a cellular genome-wide association approach to characterize a locus near the TLR10/TLR1/TLR6 region that is associated with levels of Chlamydia-induced cytokines, interacts with the TLR6 promoter, and contributes to differences among populations.
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影响因子：
3
作者：
Cunningham K;Stansfield SH;Patel P;Menon S;Kienzle V;Allan JA;Huston WM
通讯作者：
Huston WM
DOI：
10.1016/0090-1229(86)90134-0
发表时间：
1986-02-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
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作者：
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通讯作者：
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DOI：
10.1038/nrg3575
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2014-01
期刊：
Nature reviews. Genetics
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DOI：
10.1093/database/bax028
发表时间：
2017-01-01
期刊：
Database : the journal of biological databases and curation
影响因子：
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作者：
Fishilevich S;Nudel R;Rappaport N;Hadar R;Plaschkes I;Iny Stein T;Rosen N;Kohn A;Twik M;Safran M;Lancet D;Cohen D
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Cohen D
影响因子：
3.4
作者：
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通讯作者：
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