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心分子。其独特的化学性质使其成为一种 多种生物反应中的辅助因子。血红素也是人体内铁的重要来源。 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 用亚铁血红素环释放铁。后一种反应是由称为血红素的蛋白质催化的。 降解酶(HDE)。因为它们具有释放铁的特性，而且 铁在细菌生理中的作用，HDE在哺乳动物感染过程中起着至关重要的作用 主持人。 炭疽芽胞杆菌是炭疽病的病原体，是一种 生物恐怖主义的武器。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 因此可以作为铁摄取的模型。以前对这种病原体的研究发现了一种 进口宿主血红素的表面和分泌血球的优雅系统。生物学的 从这种病原体的生命周期来看，进口血红素的后果尚未得到证实 下定决心。这里提供的初步数据表明，炭疽杆菌编码三种不同的 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B。 炭疽病将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都很重要 炭疽杆菌感染。在目标1中，吸入性感染模型，最严重的临床形式， 用来确定每种HDE对炭疽病的贡献。在目标2中，功能 每个HDE的作用在三个重要的宿主利基中被探测到：通过以下方式防止宿主死亡 肺泡巨噬细胞、过量血红素的解毒和宿主铁的利用 血液中的血红蛋白。这些研究将确定HDE是否是抗炭疽热的目标，以及在 芽孢杆菌的感染循环它们起作用。