INTRACELLULAR IRON UPTAKE BY MYCOBACTERIA

这项研究的长期目标是在生物化学和遗传方面 描述细胞内使用的潜在毒力因子 分枝杆菌从宿主细胞获取铁。 哺乳动物有一种抗感染系统，它试图阻止 生物必需的金属铁免受入侵微生物的侵袭，但“铁- 抑制“防御”可能是对抗细胞外最有效的防御 病原体。另一种可能的防御系统(称为“缺铁”) 因为它包括从受感染的宿主细胞流出的非血红素铁)可能 对寄主细胞内的病原体起作用。成功的病原体 必须通过包括有效的铁获取来克服这些障碍 在它们的毒力特性中。铁载体的生产是一种常见的铁 微生物采集策略及在分枝杆菌体外培养中的应用 在细胞内，铁载体(Mycobactin)介导的铁摄取系统是 为人所知。然而，关于铁的获取机制的信息很少。 由巨噬细胞吞噬小体中的分枝杆菌使用。Mycobactin可能不 对细胞内铁的吸收是必不可少的，因为致病的真菌- 已知缺乏产生mycobactin的细菌菌株。假说 未知的细胞内铁摄取机制(S)可能是 对分枝杆菌的毒力至关重要。具体目标是：1. 建立准确的分枝杆菌/巨噬细胞培养体系 监测吞噬体内存在的分枝杆菌中铁的流动，2. 鉴定和表征分枝杆菌因子和过程，如 以及编码这些物质的合成的基因，这些基因对于 细胞内的铁摄取。

The long-term goals of the research are to biochemically and genetically characterize the potential virulence factors used by intracellular mycobacteria to acquire iron from host cells. Mammals have an anti-infective system that attempts to withhold the biologically essential metal iron from invading microbes, but the "iron- withholding" defenses may be most effective against extracellular pathogens. Another possible defense system (called "iron-depletion" because it includes efflux of non-heme iron from infected host cells) may operate against pathogens living inside host cells. Successful pathogens must overcome these barriers by including effective iron acquisition among their virulence properties. Siderophore production is a common iron gathering tactic of microbes and in mycobacteria cultured extra- cellularly, a siderophore (mycobactin)-mediated iron uptake system is known. However, there is scant information on iron acquisition mechanisms used by mycobacteria present in macrophage phagosomes. Mycobactin may not be essential for intracellular iron uptake because pathogenic myco- bacterial strains lacking mycobactin production are known. The hypothesis is that the unidentified intracellular iron uptake mechanism(s) may be crucial for virulence of mycobacteria. The specific aims are: 1. to establish a mycobacteria/macrophage culture system that will accurately monitor the flow of iron to mycobacteria present within phagosomes, 2. to identify and characterize the mycobacterial factors and processes, as well as the genes encoding synthesis of these, that are essential for intracellular iron uptake.