Nutrient Uptake during Anthrax Disease

炭疽病期间的营养吸收

• 批准号: 10296654
• 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 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10296654
• 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.

项目摘要 致病细菌需要获取必需的营养素，以在其中建立和维持感染 主持人。宿主限制了获得这种营养的机会，这是一种称为营养免疫的概念。像这样， 细菌养分进口系统以及控制它们的代谢调节剂，代表接下来 新型抗菌剂的产生靶标。革兰氏阳性细菌B.炭疽病是病因 炭疽病和生物恐怖主义的武器。该病原体具有显着的能力 在脊椎动物中复制，该美德对于研究细菌如何克服营养很有用 免疫。众所周知， 分支氨基酸的生物合成的倒数第二步 对于所有生命都是必要的，需要一种活性取决于铁硫簇的酶。 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聪明 代谢机制，以控制分支氨基酸的摄入量与 在复杂的宿主环境中维持铁稳态。在前提下工作 当外铁水平较低时，芽孢杆菌是缬氨酸的可营养性，因此无法进行分支 氨基酸，我们假设从血液蛋白释放的宿主瓣膜刺激了铁的采集 通过革兰氏阳性细菌中毒力的全球调节剂Cody。这反过来促进了进口 铁，从而减轻了宿主血液和组织中的合理营养丰富的快速复制。目标 1个项目，我们报告了一种新型分支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的习得中的作用。在AIM 2中，我们调查了 从血红素释放的铁通过两种新发现的芽孢杆菌中的血红素结合酶释放的机理。 最后，在AIM 3中，我们整合了中心模型的关键方面，以确定这些重要性 在炭疽疾病期间发育的芽孢杆菌感染的每个步骤中。由于这个网络 营养摄取系统和调节剂在几种具有临床意义的物种中也具有同源物， 这里的工作将提供有关致病细菌如何促进其新陈代谢的基本知识 毒力。

项目成果

Iron and zinc exploitation during bacterial pathogenesis.

• DOI: 10.1039/c5mt00170f
• 发表时间: 2015-12
• 期刊: Metallomics : integrated biometal science
• 作者: Ma L;Terwilliger A;Maresso AW
• 通讯作者: Maresso AW

Global metabolomic analysis of a mammalian host infected with Bacillus anthracis.

感染炭疽杆菌的哺乳动物宿主的整体代谢组学分析。

• DOI: 10.1128/iai.00947-15
• 发表时间: 2015
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Nguyen,ChinhTQ;Shetty,Vivekananda;Maresso,AnthonyW
• 通讯作者: Maresso,AnthonyW

Loss of Dihydroxyacid Dehydratase Induces Auxotrophy in Bacillus anthracis.

二羟酸脱水酶的丧失会导致炭疽杆菌营养缺陷型。

• DOI: 10.1128/jb.00415-21
• 发表时间: 2021
• 期刊: Journal of bacteriology
• 影响因子: 3.2
• 作者: Jelinski,Joseph;Cortez,Madeline;Terwilliger,Austen;Clark,Justin;Maresso,Anthony
• 通讯作者: Maresso,Anthony

Bacillus anthracis Overcomes an Amino Acid Auxotrophy by Cleaving Host Serum Proteins.

炭疽芽孢杆菌通过裂解宿主血清蛋白来克服氨基酸营养缺陷型。

• DOI: 10.1128/jb.00073-15
• 发表时间: 2015
• 期刊: Journal of bacteriology
• 影响因子: 3.2
• 作者: Terwilliger,Austen;Swick,MichelleC;Pflughoeft,KathrynJ;Pomerantsev,Andrei;Lyons,CRick;Koehler,TheresaM;Maresso,Anthony
• 通讯作者: Maresso,Anthony

Molecular and evolutionary analysis of NEAr-iron Transporter (NEAT) domains.

NEAr-铁转运蛋白 (NEAT) 结构域的分子和进化分析。

• DOI: 10.1371/journal.pone.0104794
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Honsa,ErinS;Maresso,AnthonyW;Highlander,SarahK
• 通讯作者: Highlander,SarahK