Role of iron efflux in Salmonella pathogenesis

描述(由申请人提供)：我们相信铁稳态的控制对鼠伤寒沙门氏菌在宿主巨噬细胞内遇到的氧化和亚硝化压力中生存下来至关重要。在芬顿反应中，铁可以与过氧化氢相互作用形成剧毒的羟基或铁自由基。为了证实我们的观点，铁的动态平衡对细菌的生存至关重要，一个缺乏下调铁摄取能力的鼠伤寒沙门氏菌皮毛突变体增加了细胞内的铁，当在最低限度的培养基中生长时，比野生型更容易受到过氧化氢的影响。令人惊讶的是，与野生型沙门氏菌相比，同样的突变株在富含铁的介质中生长时并没有表现出更高的敏感度，而且实际上，铁含量非常相似。这些结果表明，存在一种非毛皮依赖的机制来控制细胞内的铁水平。我们已经确定了一个编码假定运输蛋白的候选操纵子。这项建议的目的是进一步确定yegMNOB操纵子的特征，并确定其在小鼠模型中控制铁稳态、对氧化和亚硝化应激的抗性以及毒力方面的作用。这些研究将为细菌用来控制细胞内铁水平的机制提供新的见解，并将进一步加深我们对鼠伤寒沙门氏菌用来规避宿主防御的致病机制的理解。

DESCRIPTION (provided by applicant): It is our belief that control of iron homeostasis is crucial to the ability of Salmonella typhimufium to survive the oxidative and nitrosative stresses encountered within host macrophages, iron can interact with hydrogen peroxide to form highly toxic hydroxyl or ferryl radicals during the Fenton reaction. In confirmation of our idea that iron homeostasis is crucial for bacterial survival, a S. typhimurium fur mutant, which is deficient in its ability to down-regulate iron uptake, has increased intracellular iron and is more susceptible than wild type, to hydrogen peroxide, when grown in minimal medium. Surprisingly, this same mutant when grown in rich medium does not exhibit increased sensitivity as compared to wild type Salmonella, and in fact, had very similar iron content. These results suggested that a fur-independent mechanism exists to control intracellular iron levels. We have identified a candidate operon encoding putative transport proteins. It is the goal of this proposal to further characterize the yegMNOB operon and ascertain its role in controlling iron homeostasis, resistance to oxidative and nitrosative stresses, and virulence in the murine model. These studies will provide new insights into the mechanisms utilized by bacteria to control intracellular iron levels, and will further our understanding of the pathogenic mechanisms used by S. typhimurium to circumvent host defenses.