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中央分子。它独特的化学特性使其成为 多种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，细菌使用表面蛋白进口宿主血红素，然后打破 血红素戒指释放铁。后一种反应被称为血红素的蛋白催化 降解酶（HDES）。由于它们的铁燃料特性和重要性 铁在细菌生理学中，HDE在哺乳动物感染期间已成为至关重要的 主持人。 孢子细菌B.炭疽菌是炭疽病和A的病因 生物恐怖主义的武器。该革兰氏阳性杆在脊椎动物宿主中生长到非凡的水平 因此是铁吸收的模型。这种病原体的先前工作发现了 进口宿主血红素的表面和分泌嗜血剂的优雅系统。生物学 血红素在这种病原体的生命周期中的导入后果尚未 决定。此处介绍的初步数据表明B.炭疽病编码三个不同的 HDE，所有这些都分解了血红素。这一发现提出了一个有趣的问题。 炭疽病需要三个看似多余的HDE。 这里建议在开发的不同阶段中，每个HDE可能很重要 B.炭疽病感染。在AIM 1中，感染的吸入模型，是最严重的临床形式， 用于确定每个HDE对炭疽疾病的贡献。在AIM 2中，功能性 每个HDE的作用都在三个重要的主机壁ches中进行探测：防止宿主杀死 肺泡巨噬细胞，过量血红素的排毒和宿主的铁的利用 血红蛋白在血液中。这些研究将确定HDE是否是反疫次目标以及在哪里 它们起作用的芽孢杆菌感染周期。