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：
7540938
负责人：
ROY M ROOP
金额：
$ 30.54万
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/7540938
关键词：
Attenuated Attenuated Vaccines Bacteria Bioterrorism Bordetella Brucella Brucella abortus Brucella melitensis Brucellosis Cells Chemistry Development Disease Environment Erythrocytes Eukaryota 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 Phagocytes Physiological Play Process Production Prokaryotic Cells Proteins Recycling Regulation Relative (related person)Repression Research Research Personnel Resistance Role Shigella dysenteriae Source Study Section Surveys System Testing Toxic effect Vaccines Virulence aged base cell injury deprivation experience heme a insight iron metabolism macrophage meetings microbial mouse model mutant novel pathogen prevent programs public health relevance residence uptake vaccine candidate

项目摘要

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 Vwork together with BhuA to form a functional heme transporter in 6. abortus 2308; b) to determine the relative contributions of BhuA and BhuTUV to the virulence of 6. 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.

宿主巨噬细胞在吞噬体区室中的长期停留对于巨噬细胞的能力至关重要。布鲁氏菌属从而产生疾病。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。由于巨噬细胞在细胞中的核心作用红细胞的降解以及受损细胞释放的血红蛋白和血红素的清除，血红素可能是布鲁氏菌在细胞内居住期间的重要铁源。宿主吞噬细胞。两个基因位点（称为 bhuA 和 bhuTUV），其产物预计为已在 B. abortus 2308 中鉴定出参与利用血红素作为铁源的成分，并初步确定流产 B. abortus bhuA 突变体的表征表明，这种血红素转运蛋白在对小鼠的毒力。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 一起形成 6. abortus 2308 中的功能性血红素转运蛋白； b) 确定 BhuA 的相对贡献和 BhuTUV 对小鼠模型中 6. abortus 2308 的毒力； c) 定义铁的性质和第2308章增加我们对布鲁氏菌属所采用机制的基本了解。以及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重要性血红素和含血红素化合物作为该环境中微生物病原体的铁源。此外，这些研究应该提供对布鲁氏菌所采用的调节机制的深入了解。防止铁中毒，这可能与其他依赖铁的革兰氏阴性细菌使用的方法不同铁吸收调节剂（Fur）的活性。拟议的研究具有公共卫生相关性，因为他们可以提供适合作为新型活疫苗候选物进行测试的减毒菌株。虽然布鲁氏菌属是重要的人畜共患病病原体和潜在的生物恐怖分子，目前尚无安全有效的疫苗可以预防人类布鲁氏菌病，大量研究表明，活疫苗、目前，减毒布鲁氏菌菌株为开发这种疫苗提供了最大的希望。