Characterization of Heme Acquisition in Bacillus Anthracis

描述（由申请人提供）：B。炭疽是一种革兰氏阳性病原体。炭疽病的预防、治疗和治愈必须针对传染周期中的关键步骤，包括铁的摄取。本研究假设B.炭疽菌在炭疽病期间作为专用的血红素获取和运输系统发挥作用。此外，我们提出血红素是通过分泌的血细胞从血红蛋白中获得的，血细胞将卟啉传递到基于细胞壁的血红素运输系统并最终进入细胞。有两个具体目标： 1.研究isd样基因座在B.炭疽病发病机理 1.a.确定isd样基因座对B的贡献。anthracis铁收购。 将探讨的监管，本地化，并促进生长的ISD样组件。 1.b.确定isd样基因座对B的贡献。炭疽毒力 将研究突变体在动物中引起炭疽病的能力。 2.研究B中通过isd样系统获得铁的模式。炭疽病 2.a.确定从血红蛋白中获取血红素的分子机制。 将研究血红素/血红蛋白结合和提取的结构要求。 2.b.确定血红素转运到B的分子机制。炭疽病 血红素从分泌的血细胞到细胞壁的移动将被确定。 该项目的长期目标包括：（i）确定革兰氏阳性病原体在感染过程中如何获得铁;（ii）确定分选酶或血红素摄取抑制剂，以开发抗感染药物;以及（iii）产生由B组成的炭疽疫苗。炭疽表面蛋白 相关性：该提案研究了B中铁获得的机制。炭疽病的病原体。本文产生的知识将增加对细菌病原体中铁获取的理解，促进靶向这些系统的新型抗菌剂的开发，并产生用于创建针对主要生物恐怖主义威胁的更安全有效的疫苗的试剂。

DESCRIPTION (provided by applicant): B. anthracis is a Gram-positive pathogen. Prevention, treatment, and cure of anthrax disease must target key steps in the infectious cycle, including iron uptake. The hypothesis of this proposal is that the isd-like locus of B. anthracis functions as a dedicated heme acquisition and transport system during anthrax disease. Further, we propose heme is acquired from hemoglobin by a secreted hemophore which relays the porphyrin to a cell wall-based heme transport system and eventually into the cell. There are two specific aims: 1. Investigate the role of the isd-like locus in B. anthracis pathogenesis. 1.a. Determine the contribution of the isd-like locus to B. anthracis iron acquisition. The regulation, localization, and contribution to growth of Isd-like components will be explored. 1.b. Determine the contribution of the isd-like locus to B. anthracis virulence. Mutants will be investigated for their ability to cause anthrax disease in animals. 2. Investigate the mode of iron acquisition via the isd-like system in B. anthracis. 2.a. Determine the molecular mechanism of heme acquisition from hemoglobin. The structural requirements for heme/hemoglobin binding and extraction will be studied. 2.b. Determine the molecular mechanism of heme transport into B. anthracis. The movement of heme from a secreted hemophore to the cell wall will be determined. The long-term objectives of this project include: (i) defining how Gram-positive pathogens acquire iron during infection (ii) identifying inhibitors of sortase or heme uptake for antiinfective development, and (iii) generating an anthrax vaccine composed of the B. anthracis surface proteins. RELEVANCE: This proposal investigates the mechanism of iron acquisition in B. anthracis, the causative agent of the disease anthrax. Knowledge generated herein will increase the understanding of iron acquisition in bacterial pathogens, facilitate the development of novel antibacterials targeting these systems, and generate reagents for the creation of a more safe and effective vaccine against a major bioterrorism threat.