Brucella Iron Metabolism in Host Macrophages

宿主巨噬细胞中的布鲁氏菌铁代谢

基本信息

批准号：
7174715
负责人：
ROY M ROOP
金额：
$ 31.13万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7174715
关键词：
Attenuated Attenuated Vaccines Bacteria Bioterrorism Bordetella Brucella Brucella abortus Brucella melitensis Brucellosis Cells Chemistry Condition Development Disease Environment Erythrocytes Eukaryota Eukaryotic Cell Exhibits Genes Genetic Genome Goals Gram-Negative Bacteria Heme Heme Iron Hemoglobin Homologous Gene Human Hydroxyl Radical In Vitro Iron Life Link Microbe Mus Nature Personal Satisfaction Phagocytes Physiological Play Process Production Prokaryotic Cells Proteins Public Health Recycling Regulation Relative (related person)Repression Research Research Personnel Resistance Role Shigella dysenteriae Source Study Section Surveys System Testing Toxic effect Vaccines Virulence Work aged base cell injury deprivation experience heme a insight iron metabolism macrophage microbial mouse model mutant novel pathogen prevent programs residence uptake

项目摘要

DESCRIPTION (provided by applicant): Prolonged residence in the phagosomal compartment of host macrophages is critical to the ability of the Brucella spp. to produce disease. Within this environment, the brucellae must resist iron deprivation. B. abortus 2308 can utilize heme as an iron source in vitro. Due to the central role of macrophages in the degradation of erythrocytes and the scavenging of hemoglobin and heme released from damaged cells, heme may represent an important iron source for the brucellae during their intracellular residence in these host phagocytes. Two genetic loci (designated bhuA and bhuTUV) whose products are predicted to be involved in the utilization of heme as an iron source have been identified in B. abortus 2308 and preliminary characterization of a B. abortus bhuA mutant suggests that this heme transporter plays a critical role in virulence in mice. Consequently, the specific aims of the studies outlined in this application are a) to confirm that the products of the genes that we have designated as bhuT, U and V work together with BhuA to form a functional heme transporter in B. abortus 2308; b) to determine the relative contributions of BhuA and BhuTUV to the virulence of B. abortus 2308 in the mouse model; and c) to define the nature of the iron- and heme-responsive regulation of bhuA and bhuTUV in the B. abortus 2308. The proposed studies should increase our basic understanding of the mechanisms employed by the Brucella spp. and other intracellular pathogens to meet their physiologic need for iron in the host. They should also better define the importance of heme and heme-containing compounds as iron sources for microbial pathogens within this environment. In addition, these studies should provide insight into the regulatory mechanisms employed by the brucellae to prevent iron toxicity, which may be different from those used by other Gram-negative bacteria that rely on the activity of the ferric uptake regulator (Fur). The proposed studies have public health relevance because they may provide attenuated bacterial strains suitable for testing as novel, live vaccine candidates. Although the Brucella spp. are important zoonotic pathogens and potential bioterrorism agents, there is presently no safe and effective vaccine to prevent human brucellosis, and numerous studies have shown that live, attenuated Brucella strains presently offer the greatest promise for the development of such a vaccine.

描述（由申请人提供）：在宿主巨噬细胞的吞噬体区室中的长期停留对于布鲁氏菌属的能力至关重要。从而产生疾病。在这种环境下，布鲁氏菌必须抵抗缺铁。 B. abortus 2308 可以在体外利用血红素作为铁源。由于巨噬细胞在红细胞降解和清除受损细胞释放的血红蛋白和血红素中的核心作用，血红素可能代表布鲁氏菌在这些宿主吞噬细胞的细胞内停留期间的重要铁源。已在流产 B. abortus 2308 中鉴定出两个基因位点（指定为 bhuA 和 bhuTUV），其产物预计参与血红素作为铁源的利用，并且流产 B. abortus bhuA 突变体的初步表征表明，该血红素转运蛋白发挥着对小鼠的毒力起关键作用。因此，本申请中概述的研究的具体目的是 a) 确认我们指定为 bhuT、U 和 V 的基因产物与 BhuA 一起在流产 B. abortus 2308 中形成功能性血红素转运蛋白； b) 确定 BhuA 和 BhuTUV 对小鼠模型中 B. abortus 2308 毒力的相对贡献； c) 确定流产布鲁氏菌 2308 中 bhuA 和 bhuTUV 的铁和血红素响应调节的性质。拟议的研究应增加我们对布鲁氏菌属所采用机制的基本了解。和其他细胞内病原体，以满足宿主对铁的生理需求。他们还应该更好地定义血红素和含血红素化合物作为该环境中微生物病原体铁源的重要性。此外，这些研究应深入了解布氏杆菌预防铁毒性的调节机制，这可能与其他依赖铁吸收调节剂（Fur）活性的革兰氏阴性菌所使用的调节机制不同。拟议的研究具有公共卫生相关性，因为它们可能提供适合作为新型活疫苗候选物进行测试的减毒细菌菌株。虽然布鲁氏菌属。布鲁氏菌是重要的人畜共患病原体和潜在的生物恐怖分子，目前还没有安全有效的疫苗来预防人类布鲁氏菌病，大量研究表明，活的减毒布鲁氏菌菌株目前为开发这种疫苗提供了最大的希望。