Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31077 Toulouse, France.
CNRS, Inserm, Centre Hospitalier Universitaire Lille, Institut Pasteur de Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, University of Lille, 59000 Lille, France.
Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):11205-11210. doi: 10.1073/pnas.1707840114. Epub 2017 Oct 2.
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 circumvents host immune defenses, we used a transposon mutant library generated in a virulent clinical isolate of 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-κB, a key regulator of innate immunity. We identified several mutants inducing a NF-κB 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-κB activation and subsequent cytokine production or costimulatory molecule expression by acting as competitive antagonists of Toll-like receptor 2, thereby inhibiting the recognition of by this receptor. Our study reveals that producing glycolipid antagonists of pattern recognition receptors is a strategy used by to undermine innate immune defense. Sulfoglycolipids are major and specific lipids of , considered for decades as virulence factors of the bacilli. Our study uncovers a mechanism by which they may contribute to virulence.
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。特别是，它抑制先天免疫反应的几个分支，包括吞噬体成熟或细胞因子产生。为了更好地理解 逃避宿主免疫防御的分子机制，我们使用了在 W/Beijing 家族的毒力临床分离株中生成的转座子突变体文库来感染人类巨噬细胞，利用表达转录因子 NF-κB 激活报告系统的 THP-1 细胞系衍生物作为先天免疫的关键调节剂。我们鉴定了几个诱导 NF-κB 激活比野生型菌株更强的 突变体。其中一个突变体被发现缺乏细胞包膜糖脂的合成，即硫酸糖脂，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，我们确定硫酸糖脂通过作为 Toll 样受体 2 的竞争性拮抗剂来抑制 NF-κB 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 的识别。我们的研究揭示了产生模式识别受体的糖脂拮抗剂是 破坏先天免疫防御的一种策略。硫酸糖脂是 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 的毒力的一种机制。
