Iron Homeostasis in Salmonella-Host Interactions

少年派：方铁卫；授予#1R01AI 77629-01A2 修订后的摘要部分 铁对几乎所有形式的生命都是必不可少的，并在细胞内发挥核心作用。 新陈代谢。微生物已经为获取制定了复杂的策略， 铁的储存、贩运、利用和解毒。其中一个主要的 铁的生化作用是作为一种中间电子载体。 含铁硫簇的蛋白质催化的氧化反应。我们的 中心假说是先天免疫利用微生物铁 靶向必需微生物铁和含铁的依赖 具有吞噬细胞衍生的活性氧和氮物种的蛋白质。 本项目将研究我们拥有的一种新型BaeSR调节外排泵 发现了当细胞内铁水平为 从铁硫团簇伤害中提升。这项研究的具体目的 计划分析沙门氏菌BaeSR系统的以下几个方面 Entreica： (1)BaeSR的激活和BaeSR调节子的特性； (2)寻找引起铁外流的新型络合剂； (3)BaeSR调节子在铁稳态和沙门氏菌中的重要性 致命性。 这项工作将对理解这些策略具有根本意义。 病原微生物通过最小化铁来逃避先天免疫-- 依赖细胞损伤和维持铁稳态。

PI: Ferric Fang; Grant # 1R01AI 77629-01A2 Revised Abstract Section Iron is essential for virtually all forms of life and plays a central role in cellular metabolism. Microbes have developed complex strategies for the acquisition, storage, trafficking, utilization and detoxification of iron. One of the primary biochemical roles of iron is to serve as an intermediate electron carrier in oxidative reactions catalyzed by proteins containing iron-sulfur clusters. Our central hypothesis is that innate immunity exploits microbial iron dependence by targeting essential microbial iron and iron-containing proteins with phagocyte-derived reactive oxygen and nitrogen species. This project will examine a novel BaeSR-regulated efflux pump we have discovered which mediates iron excretion when intracellular iron levels are elevated from iron-sulfur cluster damage. The specific aims of this research plan are to analyze the following aspects of the BaeSR system in Salmonella enterica: (1) Activation of BaeSR and characterization of the BaeSR regulon; (2) Identification of the novel chelator responsible for iron efflux; (3) Importance of the BaeSR regulon in iron homeostasis and Salmonella virulence. This work will have fundamental implications for understanding the strategies by which pathogenic microbes evade innate immunity by minimizing iron- dependent cell damage and maintaining iron homeostasis.