Mycobacterium tuberculosis inhibits human innate immune responses via the production of TLR2 antagonist glycolipids
Mycobacterium tuberculosis inhibits human innate immune responses via the production of TLR2 antagonist glycolipids
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DOI：
10.1073/pnas.1707840114
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发表时间：
2017-10-17
影响因子：
11.1
通讯作者：
Nigou, Jerome
中科院分区：
文献类型：
--
作者：
Blanc, Landry;Gilleron, Martine;Nigou, Jerome
结核分枝杆菌是一种主要的人类病原体，能够在宿主细胞内存活并抵抗免疫清除。最特别的是，它抑制了先天免疫反应的几个方面，包括吞噬体成熟或细胞因子的产生。为了更好地了解结核分枝杆菌绕过宿主免疫防御的分子机制，我们利用W/Beijing家族结核分枝杆菌临床毒力分离株中产生的转座子突变文库感染人巨噬细胞，利用THP-1细胞的细胞系衍生物表达激活转录因子NF-kappa B的报告系统，NF-kappa B是先天免疫的关键调节因子。我们发现了几种结核分枝杆菌突变体诱导NF-kappa B激活比野生型菌株更强。其中一个突变体被发现缺乏细胞包膜糖脂的合成，即巯基糖脂，这表明后者可以干扰先天免疫反应。使用天然和合成的分子变体，我们确定巯基糖脂通过作为toll样受体2的竞争性拮抗剂抑制NF-kappa B的激活和随后的细胞因子产生或共刺激分子表达，从而抑制该受体对结核分枝杆菌的识别。我们的研究表明，产生模式识别受体的糖脂拮抗剂是结核分枝杆菌用来破坏先天免疫防御的一种策略。硫糖脂是结核分枝杆菌的主要和特异性脂质，几十年来被认为是杆菌的毒力因子。我们的研究揭示了它们可能有助于结核分枝杆菌毒力的机制。
Mycobacterium tuberculosis is a major human pathogen that is able to survive inside host cells and resist immune clearance. Most particularly, it inhibits several arms of the innate immune response, including phagosome maturation or cytokine production. To better understand the molecular mechanisms by which M. tuberculosis circumvents host immune defenses, we used a transposon mutant library generated in a virulent clinical isolate of M. tuberculosis of the W/Beijing family to infect human macrophages, utilizing a cell line derivative of THP-1 cells expressing a reporter system for activation of the transcription factor NF-kappa B, a key regulator of innate immunity. We identified several M. tuberculosis mutants inducing a NF-kappa B activation stronger than that of the wild-type strain. One of these mutants was found to be deficient for the synthesis of cell envelope glycolipids, namely sulfoglycolipids, suggesting that the latter can interfere with innate immune responses. Using natural and synthetic molecular variants, we determined that sulfoglycolipids inhibit NF-kappa B activation and subsequent cytokine production or costimulatory molecule expression by acting as competitive antagonists of Toll-like receptor 2, thereby inhibiting the recognition of M. tuberculosis by this receptor. Our study reveals that producing glycolipid antagonists of pattern recognition receptors is a strategy used by M. tuberculosis to undermine innate immune defense. Sulfoglycolipids are major and specific lipids of M. tuberculosis, considered for decades as virulence factors of the bacilli. Our study uncovers a mechanism by which they may contribute to M. tuberculosis virulence.