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Branched Chain Amino Acid Metabolism During Anthrax

炭疽病期间的支链氨基酸代谢

基本信息

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
项目类别：
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

项目摘要

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.

项目总结