The Pyruvate-Tricarboxylic Acid Cycle Node A FOCAL POINT OF VIRULENCE CONTROL IN THE ENTERIC PATHOGEN YERSINIA PSEUDOTUBERCULOSIS
The Pyruvate-Tricarboxylic Acid Cycle Node A FOCAL POINT OF VIRULENCE CONTROL IN THE ENTERIC PATHOGEN YERSINIA PSEUDOTUBERCULOSIS
复制标题
DOI：
10.1074/jbc.m114.581348
复制
发表时间：
2014-10-24
影响因子：
4.8
通讯作者：
Wittmann, Christoph
中科院分区：
文献类型：
--
作者：
Buecker, Rene;Heroven, Ann Kathrin;Wittmann, Christoph
背景：假结核耶尔森菌是人类的一种病原菌，是耶尔森氏菌的祖先。鼠疫结果：Y.假结核病是其毒力控制系统的焦点。结论：在该代谢控制点遗传干扰的突变体在小鼠感染研究中毒性较低。重要性：了解致病性状是如何被控制的对于寻找针对病原体的新药物靶点至关重要。尽管我们对细菌中特定致病因子的了解越来越多，但代谢过程对毒力的贡献在很大程度上是未知的。在这里，我们阐明了致病性和核心代谢之间的紧密联系，在肠道病原体假结核耶尔森氏菌的野生型和毒力调节突变体的整合转录组和[C-13]通量体分析。在葡萄糖的有氧生长过程中，Y.假结核病揭示了一个不寻常的流量分布与高水平的分泌丙酮酸。转录和转录后调节因子RovA，CsRA和Crp的存在强烈干扰丙酮酸代谢和三羧酸（TCA）循环水平上的碳核代谢通量，这些干扰伴随着相应酶的转录变化。敲除该代谢分支点及其中心酶丙酮酸激酶（pykF）的调节剂，导致在口服小鼠感染模型中具有显著降低的毒力的突变体。综上所述，我们的工作确定了作为控制耶尔森氏菌的宿主定植和毒力的焦点的三氯乙酸-三氯乙酸循环节点。
Background:Yersinia pseudotuberculosis is a human pathogen and the ancestor of Y. pestis. Results: The pyruvate-tricarboxylic acid cycle node in the carbon core metabolism of Y. pseudotuberculosis is a focal point of its virulence control system. Conclusion: Mutants genetically perturbed at this metabolic control point are less virulent in mouse infection studies. Significance: Learning how pathogenic traits are controlled is crucial for finding novel drug targets against the pathogen.Despite our increasing knowledge of the specific pathogenicity factors in bacteria, the contribution of metabolic processes to virulence is largely unknown. Here, we elucidate a tight connection between pathogenicity and core metabolism in the enteric pathogen Yersinia pseudotuberculosis by integrated transcriptome and [C-13]fluxome analysis of the wild type and virulence-regulator mutants. During aerobic growth on glucose, Y. pseudotuberculosis reveals an unusual flux distribution with a high level of secreted pyruvate. The absence of the transcriptional and post-transcriptional regulators RovA, CsrA, and Crp strongly perturbs the fluxes of carbon core metabolism at the level of pyruvate metabolism and the tricarboxylic acid (TCA) cycle, and these perturbations are accompanied by transcriptional changes in the corresponding enzymes. Knock-outs of regulators of this metabolic branch point and of its central enzyme, pyruvate kinase (pykF), result in mutants with significantly reduced virulence in an oral mouse infection model. In summary, our work identifies the pyruvate-TCA cycle node as a focal point for controlling the host colonization and virulence of Yersinia.