The Importance and Function of Heme Degrading Enzymes during Anthrax Disease

炭疽病期间血红素降解酶的重要性和功能

• 批准号: 9323699
• 负责人: ANTHONY W MARESSO
• 金额: $ 23.78万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-23 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323699
• 关键词: Alveolar; Alveolar Macrophages; Amino Acids; Animal Model; Anthrax disease; Antibiotics; Bacillus (bacterium); Bacillus anthracis; Bacteria; Bacterial Physiology; Basic Science; Binding; Biological; Biological Assay; Biological Models; Biology; Bioterrorism; Blood; Cell Survival; Cells; Cessation of life; Clinical; Complex; Data; Development; Disease; Disease Progression; Drug Metabolic Detoxication; Electrons; Enzymes; Experimental Models; Family; Funding; Gases; Genes; Gram-Positive Rods; Growth; Heme; Heme Iron; Hemoglobin; Homeostasis; Homologous Gene; Human; Infection; Iron; Knowledge; Laboratories; Left; Life; Lung; Measures; Mediating; Membrane Proteins; Modeling; N-terminal; Natural Immunity; Nutrient; Nutritional; Pathogenesis; Phase; Physiological; Process; Production; Property; Proteins; Publishing; RNAIII; Reaction; Role; Siderophores; Source; Staphylococcus aureus; Stress; Surface; System; Testing; Tissues; Virulence; Work; chemical property; combinatorial; extracellular; heme a; killings; macrophage; member; mutant; novel; pathogen; pathogenic bacteria; porphyrin a; response; uptake; weapons

Heme is a central molecule in the biology of life. Its unique chemical properties make it a versatile co-factor in many biological reactions. Heme is also an important source of iron for bacteria. In this regard, bacteria use surface proteins to import host heme and then break the heme ring to release the iron. This latter reaction is catalyzed by proteins termed heme degrading enzymes (HDEs). Because of their iron-liberating properties and the importance of iron in bacterial physiology, HDEs have emerged as critical during the infection of mammalian hosts. The sporulating bacterium B. anthracis is the causative agent of anthrax disease and a weapon of bioterrorism. This Gram-positive rod grows to extraordinary levels in vertebrate hosts and thus serves as a model for iron uptake. Previous work with this pathogen uncovered an elegant system of surface and secreted hemophores that import host heme. The biological consequences of heme import in terms of the lifecycle of this pathogen have not been determined. Preliminary data presented here suggests B. anthracis encodes three distinct HDEs, all of which break down heme. This finding raises the interesting question as to why B. anthracis would require three seemingly redundant HDEs. It is proposed here that each HDE may be important during different phases of a developing B. anthracis infection. In Aim 1, an inhalational model of infection, the most serious clinical form, is used to determine the contribution of each HDE to anthrax disease. In Aim 2, the functional role of each HDE is probed in three important host niches: protection from host killing by alveolar macrophages, the detoxification of excess heme, and the utilization of iron from host hemoglobin in blood. These studies will determine if HDEs are anti-anthrax targets and where in the bacillus infection cycle they function.

血红素是生命生物学中的核心分子。其独特的化学性质使其成为 在许多生物反应中的多功能辅因子。血红素也是铁的重要来源， 细菌在这方面，细菌使用表面蛋白质来输入宿主血红素，然后打破血红素。 血红素环释放铁后一种反应是由血红素蛋白催化的 降解酶（HDEs）。由于其释放铁的特性以及 由于铁在细菌生理学中的作用，HDE在哺乳动物感染过程中起着关键作用。 hosts. 产孢细菌B.炭疽是炭疽病的病原体， 生物恐怖主义武器这种革兰氏阳性杆菌在脊椎动物宿主中生长到非常高的水平 并因此用作铁摄取的模型。以前对这种病原体的研究发现了一种 一个优雅的表面系统和分泌的血细胞，输入宿主血红素。生物 血红素输入在这种病原体的生命周期方面的后果还没有被 测定这里提供的初步数据表明是B。炭疽菌编码三种不同的 HDE，所有这些都能分解血红素。这一发现提出了一个有趣的问题，为什么是B。 炭疽菌需要三个看似多余的HDE。 这里提出，每个HDE在开发的不同阶段可能是重要的。 B。炭疽感染。在目标1中，吸入性感染模型，最严重的临床形式， 用于确定每种HDE对炭疽病的贡献。在目标2中， 每个HDE在三个重要的宿主生态位中的作用进行了探讨：保护宿主免受宿主杀死 肺泡巨噬细胞、过量血红素的解毒和宿主铁的利用 血红蛋白这些研究将确定HDE是否是抗炭疽的目标，以及在哪里 细菌感染周期的作用