Effect of iron availability on Staphyloccocus aureus exoprotein production.

描述（由申请人提供）：金黄色葡萄球菌每年在美国医院感染超过120万名患者。S.金黄色葡萄球菌作为病原体的致病性部分是由于表达了大量的胞外蛋白。研究了不同寄主环境对S.金黄色葡萄球菌外蛋白尚未完全了解。一个环境线索，S。金黄色葡萄球菌在体内可能感觉到的是铁可用性的波动。本申请的中心假设是S.金黄色葡萄球菌在感染期间感知铁可用性的变化，以协调促进细菌存活的特异性外蛋白表达谱。这一假设得到了这里提供的初步数据的支持，这些数据表明S。金黄色葡萄球菌响应于铁利用率的变化而差异性地协调细胞毒素和免疫调节蛋白的表达。本申请的目的是确定S.金黄色葡萄球菌超抗原样外毒素（Staphylococcal Superantigen like exotoxins，Ssl）在金黄色葡萄球菌中的作用。使用感染的动物模型和离体原代培养模型的组合的金黄色葡萄球菌-宿主相互作用。目的二是确定铁依赖性调节外蛋白的调控系统，并阐明该系统在S。金黄色葡萄球菌发病机制我们将应用DNA结合分析、转座子筛选和微阵列的组合来促进对S.金黄色葡萄球菌外蛋白。此外，我们将确定铁敏感系统对S的贡献。金黄色葡萄球菌发病机制和铁调节的外蛋白的体内表达。 相关性：拟议的研究将调查如何S。金黄色葡萄球菌感受宿主环境以调节外蛋白的表达和这些外蛋白在金黄色葡萄球菌中的功能。金黄色葡萄球菌发病机制了解S。金黄色葡萄球菌在感染过程中协调毒力因子的表达，这些因子对宿主的作用可能揭示产生针对这种重要的人类病原体的新疗法的靶点。

DESCRIPTION (provided by applicant): Staphylococcus aureus infects more than 1.2 million patients per year in U.S. hospitals. The tremendous success of S. aureus as a pathogen is in part due to the expression of an arsenal of exoproteins. The effects of different host environments on the global expression of S. aureus exoproteins are not completely understood. One environmental cue that S. aureus likely senses in vivo is fluctuations in iron availability. The central hypothesis of this application is that S. aureus senses changes in iron availability during infection to coordinate a specific exoprotein expression profile that facilitates bacterial survival. This hypothesis is supported by the preliminary data presented here, which demonstrate that S. aureus differentially coordinates the expression of cytotoxins and immunomodulatory proteins in response to changes in iron availability. The goals of this application are to determine the molecular mechanisms by which S. aureus sensically, we will investigate the role of Staphylococcal Superantigen-like exotoxins (Ssl) in S. aureus-host interactions using a combination of animal models and ex vivo primary culture models of infection. Aim two is designed to identify the regulatory system(s) responsible for iron-dependent regulation of exoproteins and to delineate the role of this system(s) in S. aureus pathogenesis. We will apply a combination of DNA binding assays, transposon screens, and microarrays to facilitate the identification and characterization of the molecule(s) responsible for the iron-dependent expression of S. aureus exoproteins. Furthermore, we will determine the contribution of the iron-sensing system(s) to S. aureus pathogenesis and to the in vivo expression of iron-regulated exoproteins. RELEVANCE: The proposed research will investigate how S. aureus senses host environments to regulate the expression of exoproteins and the function of these exoproteins in S. aureus pathogenesis. Understanding how S. aureus coordinates the expression of virulence factors during infection and the effects of these factors on the host may uncover targets for the generation of novel therapeutics against this important human pathogen.