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 支链氨基酸（缬氨酸、亮氨酸和异亮氨酸）是生命所必需的。一些生物， 像人类一样，从饮食中获得这些氨基酸，因此缺乏制造它们的能力。 其他的，比如植物，拥有完整的生物合成机制来生产它们，当它们被释放时， 营养缺乏。一些致病菌似乎两者都有，它们产生 但也拥有介导其从环境中摄取的转运蛋白。 然而，目前还不清楚这两个武器，收购与综合，是最重要的 在脊椎动物宿主的感染过程中。在这个项目中，我们使用了B。炭疽病 炭疽病的病原体，在血液和组织中大量复制，使其成为理想的 研究营养吸收，以确定支链氨基酸代谢的重要性， 这种病原体的多阶段感染过程。在杆菌需要 从血液蛋白质的分解中释放出支链氨基酸，以维持高水平的 生长，我们假设，运输游离支链氨基酸在血清中是必要的 治疗炭疽病在目标1中，我们使用在每个臂（转运）中缺陷的同基因突变菌株， 相对于合成）的支链氨基酸代谢，以确定它们对 肺炭疽热，最致命的一种在目标2中，我们探讨了这两个手臂的确切作用 细菌感染周期的每个阶段，包括受感染的巨噬细胞内的生长 以及营养杆菌在血液和类血液环境中的快速扩张。这项工作需要 了解支链氨基酸的产生和/或转运是否代表 新的抗菌策略的可行切入点。