Iron Acquisition in Anthrax

炭疽病中铁的获取

基本信息

批准号：
8371375
负责人：
ANTHONY W MARESSO
金额：
$ 39.13万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-21 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8371375
关键词：
Accounting Affinity Am 80 Animal Model Animals Anthrax disease Assimilations Attenuated Bacillus (bacterium)Bacillus anthracis Back Bacteria Binding Biochemical Biology Bioterrorism Breathing Carrier Proteins Cavia Cell Wall Cells Code Colony-forming units Computer Simulation Cytoplasm Data Ferritin Genes Genetic Genome Germination Goals Growth Heme Hemoglobin Immunity Infection Iron Kinetics Laboratory Study Lead Lethal Dose 50 Link Mammals Mediating Membrane Membrane Proteins Modeling Molecular Mutagenesis Nutritional Phenotype Play Porphyrins Protein Binding Proteins Reproduction spores Role Siderophores Source Spectrum Analysis Surface System Tertiary Protein Structure Testing Tissues Transferrin Virulence Virulent Work combinatorial drug development heme a heme-binding protein interest macrophage milliliter pathogen pathogenic bacteria protein function research study small molecule uptake weapons

项目摘要

DESCRIPTION (provided by applicant): Bacterial pathogens must acquire iron to replicate and survive in mammalian hosts. The iron-porphyrin heme, bound to circulating hemoglobin, contains up to 80% of bodily iron. This fact has led to the hypothesis, which is backed by experimental evidence, that heme serves as a source of iron during infection. However, in the anthrax-causing bacteria B. anthracis, deletion of iron-regulated surface determinant (Isd) genes, which code for surface proteins that bind heme, did not reduce B. anthracis virulence in animal models of infection. These results suggest other factors contribute to iron uptake in this deadly pathogen. A hallmark of Isd systems is the presence of a conserved protein module termed the near-iron transporter (NEAT) domain, which mediates the transfer of heme into Gram-positive pathogenic bacteria. In silico analysis of the genome of B. anthracis indicates a non-Isd gene, designated BAS0520, is annotated to encode for a single NEAT-domain protein. The objective of this proposal is to determine if BAS0520 represents the "missing link" mediating heme uptake during anthrax infection. Specifically, we hypothesize BAS0520 is a surface protein that extracts heme from host hemoglobin, thereby promoting heme transport into the bacterial cell and enhancing iron-dependent replication in mammalian hosts. This hypothesis will be tested with two aims: 1. Determine the mechanistic function of BAS0520. Biochemical approaches will define the molecular and structural factors of the NEAT domain of BAS0520. 2. Determine the role of BAS0520 in iron acquisition and anthrax disease. Growth studies and animal infection models using fully virulent strains will be used to define which mechanisms of iron uptake are important for anthrax disease. PUBLIC HEALTH RELEVANCE: Bacterial pathogens require iron in order to replicate. The goal of this proposal is to understand how B. anthracis, a potential weapon of bioterrorism and the causative agent of anthrax disease, acquires iron during infection. Understanding how bacteria survive, grow, and spread inside mammalian hosts will lead to the discovery of new targets for drug development.

描述（由申请人提供）：细菌病原体必须获得铁以在哺乳动物宿主中复制和生存。铁 - 卟啉血红素含有循环的血红蛋白，最多包含80％的人体铁。这一事实导致了这一假设得到了实验证据的支持，即血红素是感染过程中铁的来源。然而，在引起炭疽的细菌B.炭疽菌中，铁调节的表面决定因素（ISD）基因的缺失，该基因编码结合血红素的表面蛋白质，并未降低植物b。这些结果表明，其他因素在这种致命的病原体中导致铁吸收。 ISD系统的标志是称为近铁转运蛋白（整洁）结构域的保守蛋白质模块，该结构域介导了血红素转移到革兰氏阳性的致病性细菌中。在对炭疽芽孢杆菌基因组的计算机分析中，指定的非ISD基因被指定为BAS0520，以编码单个纯域蛋白的编码。该提案的目的是确定BAS0520是否代表了炭疽感染期间血红素摄取的“缺失链接”。具体而言，我们假设BAS0520是一种表面蛋白，可从宿主血红蛋白中提取血红素，从而促进血红素转运到细菌细胞中并增强哺乳动物宿主中的铁依赖性复制。该假设将以两个目的进行检验：1。确定BAS0520的机械函数。生化方法将定义BAS0520纯域的分子和结构因子。 2。确定BAS0520在铁获取和炭疽疾病中的作用。使用完全毒性菌株的生长研究和动物感染模型将用于定义哪些铁的摄取机制对于炭疽疾病很重要。公共卫生相关性：细菌病原体需要铁才能复制。该提案的目的是了解炭疽芽孢杆菌是生物恐怖主义的潜在武器和炭疽疾病的致病药物如何获得感染期间的铁。了解细菌在哺乳动物宿主内的生存，成长和扩散将导致发现新的药物开发目标。