Iron Homeostasis in Salmonella-Host Interactions

PI：Ferric Fang;批准号1 R 01 AI 77629- 01 A2 修订摘要部分 铁对几乎所有形式的生命都是必不可少的，并且在细胞内起着核心作用。 新陈代谢.微生物已经发展出复杂的获取策略， 铁的储存、运输、利用和解毒。的一个主要 铁的生物化学作用是作为中间电子载体， 含铁硫簇的蛋白质催化的氧化反应。我们 核心假设是先天免疫利用微生物铁 通过靶向必需的微生物铁和含铁的 具有吞噬细胞衍生的活性氧和氮类的蛋白质。 本项目将研究一种新的BaeSR调节外排泵，我们有 发现当细胞内铁水平降低时， 因铁硫簇损伤而升高本研究的具体目的 计划分析沙门氏菌BaeSR系统的以下方面 肠： (1)BaeSR的激活和BaeSR调节子的表征; (2)负责铁外排的新型螯合剂的鉴定 (3)BaeSR调节子在铁稳态和沙门氏菌中的重要性 毒性。 这项工作将对理解这些战略产生根本性的影响 病原微生物通过减少铁来逃避先天免疫， 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.