Brucella Iron Metabolism in Host Macrophages

宿主巨噬细胞中的布鲁氏菌铁代谢

• 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
• 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

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（由申请方提供）：在宿主巨噬细胞吞噬体隔室中的长期停留对于布鲁氏菌的能力至关重要。产生疾病。在这种环境中，布鲁氏菌必须抵抗铁的缺乏。B。abortus 2308可以利用血红素作为体外铁源。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，血红素可能是布鲁氏菌在这些宿主吞噬细胞的细胞内驻留期间的重要铁源。已在B中鉴定了两个遗传基因座（指定为bhuA和bhuTUV），其产物被预测参与血红素作为铁源的利用。流产2308和B的初步表征。abortus bhuA突变体表明该血红素转运蛋白在小鼠中的毒力中起关键作用。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的基因的产物与BhuA一起作用以在B中形成功能性血红素转运蛋白。abortus 2308; B）以确定BhuA和BhuTUV对B毒力的相对贡献。流产2308的小鼠模型;和c）确定B中bhuA和bhuTUV的铁和血红素应答性调节的性质。流产2308.拟议的研究应增加我们对布鲁氏杆菌属所采用机制的基本了解。和其它细胞内病原体以满足它们在宿主中对铁的生理需要。他们还应该更好地定义血红素和含血红素的化合物作为这种环境中微生物病原体的铁源的重要性。此外，这些研究应该提供洞察布鲁氏菌用于防止铁毒性的调节机制，这可能不同于依赖于铁摄取调节剂（Fur）活性的其他革兰氏阴性菌所使用的机制。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。虽然布鲁氏杆菌属（Brucella spp.）是重要的人畜共患病原体和潜在的生物恐怖剂，目前还没有安全有效的疫苗来预防人类布鲁氏菌病，许多研究表明，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。