Dipartimento di Biologia e Biotecnologie C. Darwin and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza-Università di Roma, 00185 Rome, Italy.
Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):E4345-54. doi: 10.1073/pnas.1303641110. Epub 2013 Oct 28.
LPS is a potent bacterial effector triggering the activation of the innate immune system following binding with the complex CD14, myeloid differentiation protein 2, and Toll-like receptor 4. The LPS of the enteropathogen Shigella flexneri is a hexa-acylated isoform possessing an optimal inflammatory activity. Symptoms of shigellosis are produced by severe inflammation caused by the invasion process of Shigella in colonic and rectal mucosa. Here we addressed the question of the role played by the Shigella LPS in eliciting a dysregulated inflammatory response of the host. We unveil that (i) Shigella is able to modify the LPS composition, e.g., the lipid A and core domains, during proliferation within epithelial cells; (ii) the LPS of intracellular bacteria (iLPS) and that of bacteria grown in laboratory medium differ in the number of acyl chains in lipid A, with iLPS being the hypoacylated; (iii) the immunopotential of iLPS is dramatically lower than that of bacteria grown in laboratory medium; (iv) both LPS forms mainly signal through the Toll-like receptor 4/myeloid differentiation primary response gene 88 pathway; (v) iLPS down-regulates the inflammasome-mediated release of IL-1β in Shigella-infected macrophages; and (vi) iLPS exhibits a reduced capacity to prime polymorfonuclear cells for an oxidative burst. We propose a working model whereby the two forms of LPS might govern different steps of the invasive process of Shigella. In the first phases, the bacteria, decorated with hypoacylated LPS, are able to lower the immune system surveillance, whereas, in the late phases, shigellae harboring immunopotent LPS are fully recognized by the immune system, which can then successfully resolve the infection.
LPS 是一种有效的细菌效应物，与复杂的 CD14、髓样分化蛋白 2 和 Toll 样受体 4 结合后，可触发固有免疫系统的激活。肠道病原体福氏志贺菌的 LPS 是一种六酰化同工型，具有最佳的炎症活性。志贺菌病的症状是由志贺菌侵袭结肠和直肠黏膜过程中引起的严重炎症产生的。在这里，我们研究了志贺菌 LPS 在引发宿主失调的炎症反应中所起的作用。我们揭示了：（i）志贺菌能够在增殖过程中改变 LPS 的组成，例如脂 A 和核心结构域；（ii）细胞内细菌（iLPS）和实验室培养基中培养的细菌的 LPS 在脂 A 中的酰链数量上存在差异，iLPS 是低酰化的；（iii）iLPS 的免疫原性远低于实验室培养基中培养的细菌；（iv）两种 LPS 形式主要通过 Toll 样受体 4/髓样分化初级反应基因 88 途径信号传递；（v）iLPS 下调 Shigella 感染巨噬细胞中介导的白细胞介素-1β的炎症小体释放；（vi）iLPS 对多形核细胞的氧化爆发的刺激能力降低。我们提出了一个工作模型，其中两种 LPS 形式可能控制志贺菌侵袭过程的不同步骤。在最初阶段，细菌表面带有低酰化 LPS，能够降低免疫系统的监测，而在后期，具有免疫原性 LPS 的志贺菌被免疫系统完全识别，免疫系统可以成功地解决感染。
