Characterization of Heme Acquisition in Bacillus Anthracis

描述（由申请人提供）：炭疽杆菌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感染周期的关键步骤，包括铁摄取。本研究假设炭疽芽孢杆菌的isd样基因座在炭疽疾病中起着血红素获取和运输系统的作用。此外，我们提出血红素是通过分泌的血红细胞从血红蛋白中获得的，它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：

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.