Staphylococcus aureus Responds to the Central Metabolite Pyruvate To Regulate Virulence.
Staphylococcus aureus Responds to the Central Metabolite Pyruvate To Regulate Virulence.
复制标题
金黄色葡萄球菌对中央代谢物丙酮酸反应以调节毒力。
DOI：
10.1128/mbio.02272-17
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发表时间：
2018-01-23
期刊：
影响因子：
6.4
通讯作者：
Torres VJ
中科院分区：
文献类型：
--
作者：
Harper L;Balasubramanian D;Ohneck EA;Sause WE;Chapman J;Mejia-Sosa B;Lhakhang T;Heguy A;Tsirigos A;Ueberheide B;Boyd JM;Lun DS;Torres VJ
金黄色葡萄球菌是一种多种多样的细菌病原体，可导致严重的疾病负担和死亡。与其他病原体一样，金黄色葡萄球菌必须适应其环境，才能产生毒力因子，才能在感染引发的免疫反应中存活下来。尽管环境信号对金黄色葡萄球菌的致病力很重要，但只有有限数量的这些信号被详细研究，以了解它们调节毒力的能力。在这里，我们展示了丙酮酸，一种中枢代谢物，导致金黄色葡萄球菌整体代谢通量的变化，并增强了其致病性。我们证明了丙酮酸诱导毒力因子的产生，如形成孔洞的杀亮素，这种诱导导致社区获得的耐甲氧西林金黄色葡萄球菌(CA-MRSA)克隆USA300的毒力增加。具体地说，我们证明了有效的“丙酮酸反应”需要金黄色葡萄球菌主调控子AGRAC和SAERS以及ArlRS双组分系统的激活。综上所述，我们的报告进一步建立了代谢和毒力之间的强烈关系，并确定丙酮酸是通过复杂的调控网络协调金黄色葡萄球菌毒力的新的调控信号。描述宿主衍生的小分子对人类病原体组成的影响是理解宿主-病原体相互作用的一个不断发展的领域。金黄色葡萄球菌是一种重要的病原体，它定居在多达三分之一的人类人口中，并可导致严重感染，导致约15%的病例死亡。在这里，我们展示了丙酮酸，一种关键的营养和中枢代谢物，引起金黄色葡萄球菌代谢通量的全球变化，并激活调节网络，允许大幅增加杀亮氨酸的产生。这些和其他毒力因子对于金黄色葡萄球菌感染不同的宿主生态位，启动感染，并有效地颠覆宿主免疫反应至关重要。了解环境信号，特别是那些对人类宿主至关重要并突出的信号如何影响毒力，将使我们能够更好地了解致病性，并考虑更有针对性的方法来应对当前的金黄色葡萄球菌疫情。
Staphylococcus aureus is a versatile bacterial pathogen that can cause significant disease burden and mortality. Like other pathogens, S. aureus must adapt to its environment to produce virulence factors to survive the immune responses evoked by infection. Despite the importance of environmental signals for S. aureus pathogenicity, only a limited number of these signals have been investigated in detail for their ability to modulate virulence. Here we show that pyruvate, a central metabolite, causes alterations in the overall metabolic flux of S. aureus and enhances its pathogenicity. We demonstrate that pyruvate induces the production of virulence factors such as the pore-forming leucocidins and that this induction results in increased virulence of community-acquired methicillin-resistant S. aureus (CA-MRSA) clone USA300. Specifically, we show that an efficient “pyruvate response” requires the activation of S. aureus master regulators AgrAC and SaeRS as well as the ArlRS two-component system. Altogether, our report further establishes a strong relationship between metabolism and virulence and identifies pyruvate as a novel regulatory signal for the coordination of the S. aureus virulon through intricate regulatory networks. Delineation of the influence of host-derived small molecules on the makeup of human pathogens is a growing field in understanding host-pathogen interactions. S. aureus is a prominent pathogen that colonizes up to one-third of the human population and can cause serious infections that result in mortality in ~15% of cases. Here, we show that pyruvate, a key nutrient and central metabolite, causes global changes to the metabolic flux of S. aureus and activates regulatory networks that allow significant increases in the production of leucocidins. These and other virulence factors are critical for S. aureus to infect diverse host niches, initiate infections, and effectively subvert host immune responses. Understanding how environmental signals, particularly ones that are essential to and prominent in the human host, affect virulence will allow us to better understand pathogenicity and consider more-targeted approaches to tackling the current S. aureus epidemic.