Role of iron efflux in Salmonella pathogenesis

描述（由申请人提供）：我们认为，铁稳态的控制对于鼠伤寒沙门氏菌在宿主巨噬细胞内遇到的氧化和亚硝化应激中存活的能力至关重要，铁可与过氧化氢相互作用，在芬顿反应期间形成高毒性羟基或铁基自由基。为了证实我们的观点，即铁稳态对细菌的生存至关重要，一个S。当在基本培养基中生长时，缺乏下调铁摄取能力的鼠伤寒鼠皮毛突变体具有增加的细胞内铁，并且比野生型对过氧化氢更敏感。令人惊讶的是，当在丰富的培养基中生长时，该相同的突变体与野生型沙门氏菌相比没有表现出增加的敏感性，并且实际上具有非常相似的铁含量。这些结果表明，存在一种非毛皮依赖性机制来控制细胞内铁水平。我们已经确定了一个候选操纵子编码推定的运输蛋白。本提案的目标是进一步表征yegMNOB操纵子并确定其在控制铁稳态、抗氧化和亚硝化应激以及小鼠模型中的毒力中的作用。这些研究将为细菌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S.鼠伤寒沙门氏菌来规避宿主防御。

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.