CSIR - Centre for Cellular and Molecular Biology, Hyderabad, India.
FEBS J. 2014 Mar;281(6):1556-70. doi: 10.1111/febs.12723. Epub 2014 Feb 12.
The pathogenesis of Mycobacterium tuberculosis involves the coordinate action of multiple bacillary components that modulate host immune responses to ensure its survival. One such group of factors is the multigenic PE_PPE protein family, several members of which have been implicated in host immune evasion. Here we investigate the function of the PE-PPE gene pair PE35 (Rv3872)-PPE68 (Rv3873), located in the region of difference 1, encoding a specialized mycobacterial secretion system that is deleted in all vaccine strains of Mycobacterium bovis BCG. We report that this gene pair is co-operonic in M. tuberculosis, and demonstrate that its gene products interact with each other. Stimulation of THP-1 macrophages with recombinant PE35 and PPE68, singly or in combination, led to a dose-dependent increase in levels of the anti-inflammatory cytokine interleukin (IL)-10 and the chemokine monocyte chemoattractant protein-1, and caused a reciprocal decrease in levels of the proinflammatory cytokine IL-12. PE35/PPE68-stimulated production of IL-10 and monocyte chemoattractant protein-1 was observed to be dependent on toll-like receptor 2, as receptor blockade caused a significant reduction in their levels. Pharmacological inhibition indicated that this induction involved activation of the mitogen-activated protein kinase signalling axis. In a transwell migration assay, culture supernatants from PE35/PPE68-treated THP-1 cells were observed to stimulate the migration of monocytes. Our findings suggest that the PE35-PPE68 gene pair plays an important immunomodulatory role in regulating the pathophysiology of M. tuberculosis.
TLR2 physically interacts with PPE68 by anti bait coimmunoprecipitation (View interaction) PE35 binds to PPE68 by pull down (View interaction) PE35 physically interacts with PPE68 by anti tag coimmunoprecipitation (View interaction) TLR2 physically interacts with PE35 by anti bait coimmunoprecipitation (View interaction) PPE68 and PE35 physically interact by dihydrofolate reductase reconstruction (View interaction).
分枝杆菌的发病机制涉及多种细菌成分的协调作用，这些成分调节宿主的免疫反应，以确保其存活。其中一组因子是多基因 PE_PPE 蛋白家族，其中几个成员被认为参与了宿主的免疫逃避。在这里，我们研究了位于差异 1 区的 PE-PPE 基因对 PE35（Rv3872）-PPE68（Rv3873）的功能，该基因对编码一种专门的分枝杆菌分泌系统，该系统在所有牛分枝杆菌卡介苗疫苗株中缺失。我们报告说，该基因对在结核分枝杆菌中是协同的，并证明其基因产物相互作用。用重组 PE35 和 PPE68 单独或联合刺激 THP-1 巨噬细胞，导致抗炎细胞因子白细胞介素（IL）-10 和趋化因子单核细胞趋化蛋白-1 的水平呈剂量依赖性增加，并导致促炎细胞因子 IL-12 的水平相应降低。观察到 PE35/PPE68 刺激的白细胞介素（IL）-10 和单核细胞趋化蛋白-1 的产生依赖于 Toll 样受体 2，因为受体阻断导致其水平显著降低。药理抑制表明这种诱导涉及丝裂原活化蛋白激酶信号通路的激活。在 Transwell 迁移测定中，观察到 PE35/PPE68 处理的 THP-1 细胞的培养上清液刺激单核细胞的迁移。我们的研究结果表明，PE35-PPE68 基因对在调节结核分枝杆菌的病理生理学方面发挥着重要的免疫调节作用。
