INTRACELLULAR IRON UPTAKE BY MYCOBACTERIA

这项研究的长期目标是从生物化学和遗传学角度 表征细胞内使用的潜在毒力因子 分枝杆菌从宿主细胞中获取铁。 哺乳动物有一个抗感染系统，试图阻止 生物必需的金属铁从入侵的微生物，但“铁- 抑制”防御可能是最有效的对抗细胞外 病原体另一种可能的防御系统（称为“铁耗尽”） 因为它包括非血红素铁从受感染的宿主细胞流出）可以 对抗宿主细胞内的病原体成功的病原体 必须克服这些障碍，包括有效的铁收购 它们的毒性特性。铁载体生产是一种常见的铁 微生物的聚集策略和体外培养的分枝杆菌中， 在细胞内，铁载体（分枝杆菌素）介导的铁摄取系统， 知道的然而，关于铁获得机制的信息很少 由巨噬细胞吞噬体中的分枝杆菌使用。分枝杆菌素可能不会 对于细胞内铁的摄取至关重要，因为致病性真菌- 已知缺乏分枝杆菌素生产的细菌菌株。的假设 未鉴定的细胞内铁摄取机制可能是 对分枝杆菌的毒力至关重要。具体目标是：1.到 建立分枝杆菌/巨噬细胞培养系统， 监测铁流向吞噬体内存在的分枝杆菌，2. 鉴定和表征分枝杆菌因子和过程， 以及编码这些合成的基因， 细胞内铁摄取

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.