Trisaccharides of Phenolic Glycolipids Confer Advantages to Pathogenic Mycobacteria through Manipulation of Host-Cell Pattern-Recognition Receptors
Trisaccharides of Phenolic Glycolipids Confer Advantages to Pathogenic Mycobacteria through Manipulation of Host-Cell Pattern-Recognition Receptors
复制标题
DOI：
10.1021/acschembio.6b00568
复制
发表时间：
2016-10-01
影响因子：
4
通讯作者：
Astarie-Dequeker, Catherine
中科院分区：
文献类型：
--
作者：
Arbues, Ainhoa;Malaga, Wladimir;Astarie-Dequeker, Catherine
尽管分枝杆菌病原体仍然是对公共卫生的威胁，但人们对它们通过调节宿主免疫反应而持续存在的机制知之甚少。在怀疑起作用的因素中有酚糖脂（PGLs），主要由结核分枝杆菌和麻风分枝杆菌等主要病原菌产生。在这里，我们报告了一个原始的策略相结合的PGL途径的遗传重编程在牛分枝杆菌卡介苗和化学合成，以检查是否在物种特异性PGL糖的变化有模式识别受体（PRR）和感染细胞的整体反应的影响。我们鉴定了与来自M的PGLs中发现的三糖结构域相关的两个不同性质。leprae和M.结核首先，从M.麻风在其结合补体受体3（CR 3）的凝集素结构域以有效侵入人巨噬细胞的能力方面是独特的。其次，M. PGL的三糖结构域。结核和M.麻风病人都具有抑制Toll样受体2（TLR 2）触发的NF-κ B活化的能力，从而抑制炎性细胞因子的产生。一致地，发现PGL-1也结合分离的TLR 2。相比之下，来自M.牛和溃疡分枝杆菌没有表现出这种活性。总之，PGLs上延伸的糖结构域的产生决定了它们被宿主PRR识别以增强分枝杆菌感染性并破坏宿主免疫应答。
Despite mycobacterial pathogens continue to be a threat to public health, the mechanisms that allow them to persist by modulating the host immune response are poorly understood. Among the factors suspected to play a role are phenolic glycolipids (PGLs), produced notably by the major pathogenic species such as Mycobacterium tuberculosis and Mycobacterium leprae. Here, we report an original strategy combining genetic reprogramming of the PGL pathway in Mycobacterium bovis BCG and chemical synthesis to examine whether sugar variations in the species-specific PGLs have an impact on pattern recognition receptors (PRRs) and the overall response of infected cells. We identified two distinct properties associated with the trisaccharide domains found in the PGLs from M. leprae and M. tuberculosis. First, the sugar moiety of PGL-1 from M. leprae is unique in its capacity to bind the lectin domain of complement receptor 3 (CR3) for efficient invasion of human macrophages. Second, the trisaccharide domain of the PGLs from M. tuberculosis and M. leprae share the capacity to inhibit Toll-like receptor 2 (TLR2)-triggered NF-kappa B activation, and thus the production of inflammatory cytokines. Consistently, PGL-1 was found to also bind isolated TLR2. By contrast, the simpler sugar domains of PGLs from M. bovis and Mycobacterium ulcerans did not exhibit such activities. In conclusion, the production of extended saccharide domains on PGLs dictates their recognition by host PRRs to enhance mycobacterial infectivity and subvert the host immune response.