METABOLIC REGULATION OF STAPHYLOCOCCAL PATHOGENESIS

葡萄球菌发病的代谢调节

• 批准号: 7381839
• 负责人: GREG Alan SOMERVILLE
• 金额: $ 17.33万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381839
• 关键词: METABOLIC; REGULATION; STAPHYLOCOCCAL; PATHOGENESIS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Staphylococcus aureus is a Gram-positive pathogen that causes a wide variety of diseases in humans and animals. It is a leading cause of hospital acquired infections, costing the United States more than 4.5 billion dollars annually. The expression of most S. aureus virulence factors is determined by the growth phase.The exponential phase of growth is characterized by the production of cell associated adhesion factors (e.g., fibronectin binding protein) while the post-exponential phase of growth is distinguished by the production of secreted virulence factors (e.g., alpha-toxin). Concomitant with the entry into the post-exponential phase of growth is an increase in tricarboxylic acid (TCA) cycle activity. Aconitase is a TCA cycle enzyme that converts citrate to isocitrate. Eukaryotic organisms have mitochondrial and cytoplasmic aconitase activity. The cytoplasmic aconitase activity is caused by the iron-responsive protein-1 (IRP-1), an mRNA-binding protein that posttranscriptionally regulates the synthesis of iron-regulated proteins. Thus, cytosolic aconitase is a bifunctional protein. Recently, it has been demonstrated that aconitase from Bacillus subtilis and Escherichia coli bind to sequence specific-elements in mRNAs in an iron-dependent fashion. These observations established bacterial aconitase, like eukaryotic cytosolic aconitase/IRP-1, as a bifunctional protein. Inactivation of the sole S. aureus aconitase gene (acnA/citB), significantly decreases virulence factor synthesis, alters host-pathogen interaction, and enhances stationary phase survival. The affects of aconitase inactivation can be the result of a metabolic block in the TCA cycle, the loss of regulatory function, or a combination of the two. We propose to determine which affects of aconitase inactivation are due to a metabolic defect and which are due to the loss of regulatory function. Additionally, we will determine if aconitase will bind to the cognate mRNAs of genes identified as potentially regulated by aconitase. [Lay Summary] Bacteria are single celled organisms that "eat" and divide; therefore, everything bacteria do is linked to eating and dividing, including causing disease in humans. A fundamental understanding of how bacteria regulate pathogenesis in response to nutrient limitation is critical to developing new treatments designed to kill bacteria. The work contained within this proposal is a first step in designing new strategies to combat bacterial infections.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。金黄色葡萄球菌是一种革兰氏阳性病原体，可引起人类和动物的多种疾病。它是医院获得性感染的主要原因，每年给美国造成的损失超过 45 亿美元。大多数金黄色葡萄球菌毒力因子的表达由生长阶段决定。生长的指数期的特征是细胞相关粘附因子（例如纤连蛋白结合蛋白）的产生，而生长的指数后阶段​​的特征是分泌性毒力因子（例如，α-毒素）的产生。伴随着进入指数后生长阶段的是三羧酸（TCA）循环活性的增加。乌头酸酶是一种 TCA 循环酶，可将柠檬酸转化为异柠檬酸。真核生物具有线粒体和细胞质乌头酸酶活性。细胞质乌头酸酶活性是由铁反应蛋白-1 (IRP-1) 引起的，IRP-1 是一种 mRNA 结合蛋白，可在转录后调节铁调节蛋白的合成。因此，胞质乌头酸酶是一种双功能蛋白。最近，已经证明来自枯草芽孢杆菌和大肠杆菌的乌头酸酶以铁依赖性方式与 mRNA 中的序列特定元件结合。这些观察结果表明，细菌乌头酸酶与真核胞质乌头酸酶/IRP-1 一样，是一种双功能蛋白。唯一的金黄色葡萄球菌乌头酸酶基因 (acnA/citB) 失活可显着降低毒力因子合成，改变宿主-病原体相互作用，并提高稳定期存活率。乌头酸酶失活的影响可能是 TCA 循环代谢受阻、调节功能丧失或两者兼而有之的结果。我们建议确定乌头酸酶失活的哪些影响是由于代谢缺陷造成的，哪些是由于调节功能丧失造成的。此外，我们将确定乌头酸酶是否会与被确定为可能受乌头酸酶调节的基因的同源 mRNA 结合。 [外行总结] 细菌是单细胞生物，会“吃”和分裂；因此，细菌所做的一切都与进食和分裂有关，包括引起人类疾病。对细菌如何响应营养限制而调节发病机制的基本了解对于开发旨在杀死细菌的新疗法至关重要。该提案中包含的工作是设计对抗细菌感染的新策略的第一步。