Functional Characterization of Naturally Occurring Genetic Variants in the Human TLR1-2-6 Gene Family
Functional Characterization of Naturally Occurring Genetic Variants in the Human TLR1-2-6 Gene Family
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DOI：
10.1002/humu.21486
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发表时间：
2011-06-01
期刊：
影响因子：
3.9
通讯作者：
Quintana-Murci, Lluis
中科院分区：
文献类型：
--
作者：
Ben-Ali, Meriem;Corre, Beatrice;Quintana-Murci, Lluis
toll样受体（TLRs）被认为是先天免疫系统的重要组成部分，在宿主感染后启动炎症反应。人类有10个功能性tlr，它们的亚细胞分布和它们感知的微生物激动剂不同。系统发育保守的TLR1-2-6家族的独特之处在于，TLR1和TLR6与TLR2形成异二聚体，介导对激动剂的信号传导。流行病学遗传学研究已经确定了几个TLR变异，它们似乎影响对传染病的易感性，但其功能后果在很大程度上仍然未知。在这里，我们评估了TLR1-2-6变异与氨基酸序列的改变对人类自然分离的功能影响。我们对TLR转染的人胚胎肾293T细胞用相应的TLR激动剂刺激进行NF-kappa B报告细胞实验。我们发现，在TLR1-2-6家族中发现的41个氨基酸改变的自然变异中，其中14个（5个TLR1, 4个TLR2和5个TLR6变异）表现出NF-kappa B激活的显著损伤。这些变异中的大多数以非常低的种群频率出现，并且具有种群特异性。这些观察结果表明，罕见的、非同义的TLR突变可能对免疫反应产生有害影响，因此可能在人群水平上导致对感染的复杂易感性。[j] .中国生物医学工程学报，2011,31(2):643-652。(C) 2011 Wiley-Liss, Inc。
Toll-like receptors (TLRs) are considered an essential component of the innate immune system, initiating inflammatory responses following infection of the host. Humans have 10 functional TLRs, differing in their subcellular distributions and the microbial agonists they sense. The phylogenetically conserved TLR1-2-6 family is unique in that TLR1 and TLR6 form hetero-dimers with TLR2 to mediate signalling in response to agonists. Epidemiological genetic studies have identified several TLR variants that appear to influence susceptibility to infectious diseases, but the functional consequences of which remain largely unknown. Here, we assessed the functional impact of the TLR1-2-6 variants with altered amino acid sequences segregating naturally in the human population. We used an NF-kappa B reporter assay in TLR-transfected human embryonic kidney 293T cells stimulated with the corresponding TLR agonists. We found that among the 41 naturally occurring variants with amino acid alterations identified in the TLR1-2-6 family, 14 of them (five TLR1, four TLR2, and five TLR6 variants) displayed marked impairment of NF-kappa B activation. Most of these variants are present at very low population frequencies and are population-specific. These observations suggest that rare, nonsynonymous TLR mutations are likely to have deleterious effects on immune responses and may therefore contribute to complex susceptibility to infection at the population level. Hum Mutat 32: 643-652, 2011. (C) 2011 Wiley-Liss, Inc.