Branched Chain Amino Acid Metabolism During Anthrax

炭疽病期间的支链氨基酸代谢

• 批准号: 9807632
• 负责人: ANTHONY W MARESSO
• 金额: $ 23.98万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807632
• 关键词: Amino Acid Transporter; Amino Acids; Anthrax disease; Antibiotics; Bacillus (bacterium); Bacillus anthracis; Bacteria; Biological Models; Biology; Bioterrorism; Blood; Blood Proteins; Branched-Chain Amino Acids; Carbon; Development; Diet; Disease; Environment; Enzymes; Essential Amino Acids; Family; Formulation; Gram-Positive Bacteria; Growth; Hemoglobin; Homeostasis; Human; Infection; Inhalation; Intestines; Iron; Isoleucine; Knowledge; Laboratories; Leucine; Life; Lung; Mediating; Metabolic; Metabolism; Modeling; Mutagenesis; Names; Nutrient; Nutritional Requirements; Organ; Organism; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Plants; Process; Production; Prokaryotic Cells; Proteins; Regulation; Reproduction spores; Role; Serum; Side; Source; Surface; Symptoms; System; Theft; Tissues; Vaccines; Valine; Virulence; Virulent; Work; alpha Toxin; amino acid metabolism; antimicrobial; arm; capsule; combinatorial; design; flu; genome-wide; gram positive spore forming rods; human pathogen; immunogenicity; macrophage; mortality; mutant; pathogen; pathogenic bacteria; stem; uptake

Project Summary Branched amino acids (valine, leucine, and isoleucine) are essential for life. Some organisms, like humans, acquire these amino acids from their diet and thus lack the ability to make them. Others, like plants, harbor the full biosynthetic machinery for their production and do so when nutrients are scarce. Some pathogenic bacteria seemingly do both; they have production capacity but also possess transporters that mediate their uptake from the environment. However, it is unclear which of these two arms, acquisition versus synthesis, is most important during infection of their vertebrate hosts. In this project, we employ the use of B. anthracis, the causative agent of anthrax disease whose prolific replication in blood and tissues makes it ideal for studying nutrient uptake, to determine the importance of branched amino acid metabolism to the multi-stage infectious process of this pathogen. Working under the premise that bacilli needs to liberate branched amino acids from the breakdown of blood proteins to sustain high levels of growth, we hypothesize that the transport of freed branched amino acids in serum is necessary for anthrax disease. In Aim 1, we use isogenic mutant strains deficient in each arm (transport versus synthesis) of branched amino acid metabolism to determine their overall contribution to pulmonary anthrax, the most lethal type. In Aim 2, we explore the exact role of these two arms to each stage in the infectious cycle of bacilli, including outgrowth inside infected macrophages and rapid expansion of vegetative bacilli in blood and blood-like environments. This work takes the first step towards knowing if branched amino acid production and/or transport represents a viable entry point for new antimicrobial strategies.

项目摘要 分支的氨基酸（Valine，Leucine和Isoleucine）对生命至关重要。一些生物， 像人类一样，从饮食中获取这些氨基酸，因此缺乏制造它们的能力。 其他人，例如植物，都为其生产带有完整的生物合成机械，并在 营养很少。一些致病性细菌似乎两者兼而有之。他们有生产 容量，但也具有转运蛋白，可以从环境中介导其吸收。 但是，目前尚不清楚这两个臂中的哪一个是获取与合成，这是最重要的 在感染脊椎动物宿主期间。在这个项目中，我们采用了炭疽芽孢杆菌的使用， 炭疽病的病因，其在血液和组织中多产的复制使其理想 用于研究营养摄取，以确定分支氨基酸代谢对 该病原体的多阶段感染过程。在细菌需要的前提下工作 从血液蛋白的分解中解放出分支的氨基酸以维持高水平 生长，我们假设有必要在血清中释放的分支氨基酸的运输 用于炭疽病。在AIM 1中，我们使用每个臂缺乏的等源性突变菌株（传输 分支氨基酸代谢的合成），以确定它们对 肺炭疽，最致命的型。在AIM 2中，我们探索了这两个武器的确切作用 到杆菌感染周期中的每个阶段，包括感染巨噬细胞内的产物 在血液和血液样环境中，营养杆菌的快速扩张。这项工作需要 了解分支氨基酸的产生和/或运输的第一步是 新的抗菌策略的可行切入点。