Nutrient Uptake during Anthrax Disease

炭疽病期间的营养吸收

• 批准号: 10053299
• 负责人: ANTHONY W MARESSO
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-21 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10053299
• 关键词: Amino Acid Transporter; Amino Acids; Anabolism; Animal Model; Animals; Anthrax disease; Anti-Infective Agents; Antibiotics; Assimilations; Bacillus; Bacillus anthracis; Bacteremia; Bacteria; Bacterial Physiology; Binding; Biological Models; Biology; Bioterrorism; Blood; Blood Proteins; Blood Vessels; Branched-Chain Amino Acids; Cells; Cessation of life; Complex; Coupled; Data; Disease; Environment; Enzymes; Equilibrium; Etiology; Fright; Funding; Genes; Germination; Gram-Positive Bacteria; Growth; Heme; Heme Iron; Hemoglobin; Hemorrhage; Homeostasis; Infection; Intake; Invaded; Iron; Knowledge; Left; Life; Link; Literature; Maintenance; Mediating; Medicine; Metabolic; Metabolism; Modeling; Nutrient; Nutritional; Nutritional Immunity; Pathogenesis; Pathway interactions; Process; Production; Protein Biochemistry; Proteolysis; Publishing; Regulation; Reporting; Reproduction spores; Role; Stress; Sulfur; Symptoms; System; Testing; Therapeutic; Tissues; Toxin; Vaccines; Valine; Vertebrates; Virulence; Work; antimicrobial; arm; auxotrophy; bioweapon; capsule; clinically significant; data integration; design; flu; human pathogen; immunogenicity; insight; iron metabolism; metabolomics; next generation; novel; pathogen; pathogenic bacteria; stem; uptake; weapons

Project Summary Pathogenic bacteria need to acquire essential nutrients to establish and sustain an infection in their hosts. The host restricts access to such nutrients, a concept termed nutritional immunity. As such, bacterial nutrient import systems, and the metabolic regulators that govern them, represent next- generation targets for novel antimicrobials. The Gram-positive bacterium B. anthracis is the causative agent of anthrax disease and a weapon of bioterrorism. This pathogen has a remarkable ability to replicate in vertebrates, a virtue that is useful for the study of how bacteria overcome nutritional immunity. It is well known that the penultimate step in the biosynthesis of branched amino acids, which are necessary for all life, requires an enzyme whose activity is dependent on an iron-sulfur cluster. Our published work and preliminary data suggests that B. anthracis and related species employ a clever metabolic mechanism to govern the balance between the intake of branched amino acids and the maintenance of iron homeostasis in complex host environments. Working under the premise that bacillus is auxotrophic for valine when external iron levels are low, and thus cannot make branched amino acids, we hypothesize that host valine liberated from blood proteins stimulates iron acquisition via the global regulator of virulence in Gram-positive bacteria, CodY. This in turn promotes the import of iron, thereby relieving the auxotrophy and fueling rapid replication in host blood and tissues. In Aim 1 of this project, we report the discovery of a novel branched amino acid transporter and characterize its role in the CodY-dependent stimulation of heme-iron acquisition. In Aim 2, we investigate the mechanism of iron release from heme via two newly uncovered heme-binding enzymes in bacillus. Finally, in Aim 3, we integrate key aspects of the central model to determine the importance of these systems in every step of a developing bacillus infection during anthrax disease. Since this network of nutrient uptake systems and regulators also have homologs in several clinically significant species, the work here will provide fundamental knowledge of how pathogenic bacteria fuel their metabolism during virulence.

项目概要 致病菌需要获取必需的营养物质才能在其体内建立和维持感染 主机。宿主限制对这些营养素的获取，这一概念称为营养免疫。像这样， 细菌营养输入系统以及控制它们的代谢调节器代表了下一个- 新型抗菌药物的一代目标。革兰氏阳性菌炭疽芽孢杆菌是致病菌 炭疽病的媒介和生物恐怖主义的武器。这种病原体具有非凡的能力 在脊椎动物中复制，这一优点有助于研究细菌如何克服营养 免疫。众所周知， 支链氨基酸生物合成的倒数第二步， 是所有生命所必需的，需要一种酶，其活性依赖于铁硫簇。 我们的 已发表的工作和初步数据表明，炭疽芽孢杆菌和相关物种采用了一种巧妙的方法 控制支链氨基酸摄入与代谢之间平衡的代谢机制 在复杂的宿主环境中维持铁稳态。工作前提是 当外部铁水平较低时，芽孢杆菌对缬氨酸是营养缺陷型的，因此不能产生分支 氨基酸，我们假设从血液蛋白中释放的宿主缬氨酸刺激铁的获取 通过革兰氏阳性菌毒力的全局调节因子 CodY。这反过来又促进了进口 铁，从而缓解营养缺陷并促进宿主血液和组织中的快速复制。瞄准 在该项目的第 1 部分中，我们报告了一种新型支链氨基酸转运蛋白的发现并表征 它在 CodY 依赖性刺激血红素铁获取中的作用。在目标 2 中，我们调查了 通过芽孢杆菌中两种新发现的血红素结合酶从血红素释放铁的机制。 最后，在目标 3 中，我们整合了中心模型的关键方面，以确定这些方面的重要性 炭疽病期间发展中的芽孢杆菌感染的每个步骤中的系统。自从这个网络 营养吸收系统和调节器在几个具有临床意义的物种中也有同源物， 这里的工作将提供有关病原菌如何促进其新陈代谢的基础知识 毒力。