Brucella Iron Metabolism in Host Macrophages

宿主巨噬细胞中的布鲁氏菌铁代谢

• 批准号: 7329160
• 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
• 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/7329160
• 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; aged; base; cell injury; deprivation; experience; heme a; insight; iron metabolism; macrophage; microbial; mouse model; mutant; novel; pathogen; prevent; programs; residence; uptake

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.

在宿主巨噬细胞的吞噬体区室中的延长的停留对于宿主巨噬细胞的吞噬能力是至关重要的。 布鲁氏菌产生疾病。在这种环境下，布鲁氏菌必须抵抗铁剥夺。B。 abortus 2308可以利用血红素作为体外铁源。由于巨噬细胞在肿瘤中的中心作用， 红细胞的降解和清除从受损细胞释放的血红蛋白和血红素， 血红素可能是布鲁氏菌在这些细胞内驻留期间的重要铁源。 宿主吞噬细胞两个遗传基因座（命名为bhuA和bhuTUV），其产物被预测为 在B中已经鉴定了参与血红素作为铁源的利用。流产2308和初步 表征一个B。流产bhuA突变体表明，这种血红素转运蛋白在 在小鼠中的毒性。因此，本申请中概述的研究的具体目的是a）确认 我们命名为bhuT、U和V的基因产物与BhuA一起形成了一个 功能性血红素转运体6例。流产2308; B）确定BhuA和 BhuTUV的毒力为6。流产2308;和c）确定铁的性质-和 B中bhuA和bhuTUV的血红素应答调节。流产2308.拟议的研究应 增加我们对布鲁氏菌感染机制的基本了解。和其它细胞内 病原体，以满足其生理需要的铁在主机。他们还应该更好地界定 血红素和含血红素的化合物作为该环境中微生物病原体的铁源。 此外，这些研究应提供深入了解的调控机制所采用的布鲁氏菌病 以防止铁毒性，这可能不同于其他革兰氏阴性菌所使用的那些， 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 它们可以提供适合作为新的活疫苗候选物进行测试的减毒细菌菌株。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主义制剂，目前还没有 安全有效的疫苗，以防止人类布鲁氏菌病，许多研究表明，活的， 减毒布鲁氏菌菌株目前为这种疫苗的开发提供了最大的希望。