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.
