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 许多生物反应中的多功能辅助因子。血红素也是铁的重要来源 细菌。在这方面，细菌利用表面蛋白输入宿主血红素，然后破坏 血红素环释放铁。后一个反应由称为血红素的蛋白质催化 降解酶（HDE）。由于其释放铁的特性和重要性 铁在细菌生理学中的作用，HDE 在哺乳动物感染过程中发挥着至关重要的作用 主机。 芽孢杆菌炭疽芽孢杆菌是炭疽病的病原体，也是炭疽病的致病菌。 生物恐怖主义的武器。这种革兰氏阳性杆在脊椎动物宿主中生长到非凡的水平 因此可作为铁吸收的模型。之前对这种病原体的研究发现 导入宿主血红素的表面血红素和分泌血红素的优雅系统。生物的 血红素输入对该病原体生命周期的影响尚未确定 决定。这里提供的初步数据表明炭疽芽孢杆菌编码三种不同的 HDE，所有这些都会分解血红素。这一发现提出了一个有趣的问题：为什么 B. 炭疽病需要三个看似多余的 HDE。 这里提出，每个 HDE 在发展的不同阶段可能都很重要。 B.炭疽感染。在目标 1 中，吸入性感染模型是最严重的临床形式， 用于确定每种 HDE 对炭疽病的贡献。在目标 2 中，函数 每个 HDE 在三个重要的宿主生态位中的作用进行了探讨： 肺泡巨噬细胞、过量血红素的解毒以及宿主铁的利用 血液中的血红蛋白。这些研究将确定 HDE 是否是抗炭疽靶标，以及它们在何处 它们发挥作用的杆菌感染周期。