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.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，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，每年给美国造成超过45亿美元的损失。大多数金黄色葡萄球菌毒力因子的表达是由生长阶段决定的。生长的指数阶段的特点是产生细胞相关的粘附因子（例如，纤维连接蛋白结合蛋白），而生长的后指数阶段的特点是产生分泌的毒力因子（例如，α毒素）。随着进入指数后生长阶段，三羧酸（TCA）循环活性增加。乌头酸酶是一种将柠檬酸转化为异柠檬酸的TCA循环酶。真核生物具有线粒体和细胞质乌头酶活性。胞质乌头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，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，已经证明枯草芽孢杆菌和大肠杆菌中的乌头酶以铁依赖的方式结合mrna中的特定元素序列。这些观察结果证实细菌乌头酶与真核胞质乌头酶/IRP-1一样，是一种双功能蛋白。唯一的金黄色葡萄球菌乌头酶基因（acnA/citB）失活，显著降低毒力因子合成，改变宿主-病原体相互作用，提高固定期存活率。乌头酸酶失活的影响可能是TCA循环代谢阻滞的结果，调节功能的丧失，或两者的结合。我们建议确定哪些乌头酶失活的影响是由于代谢缺陷，哪些是由于调节功能的丧失。此外，我们将确定乌头酶是否会结合被确定为可能受乌头酶调节的基因的同源mrna。【概要】细菌是“吃”和分裂的单细胞生物；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。对细菌如何调节发病机制以应对营养限制的基本理解对于开发旨在杀死细菌的新疗法至关重要。这项提案所包含的工作是设计对抗细菌感染的新策略的第一步。