Antioxidant-based mechanisms used by staphyloccocus aureus to evade host defenses

描述（由申请人提供）：金黄色葡萄球菌是一种重要的病原体，是医院和社区环境中的主要公共卫生问题。在葡萄球菌感染期间健康或疾病的中心决定因素是宿主和细菌的抗氧化和氧化还原系统。吞噬细胞的氧化爆发通过产生对入侵微生物直接有毒的活性氧（ROS）来保护宿主，但ROS也作为关键炎症信号网络中的第二信使，并干扰S.金黄色葡萄球菌毒力上调。S.金黄色葡萄球菌通过使用特定的抗氧化剂使ROS失活来反对这种策略。在这个提议中，我们假设细菌抗氧化剂的功能不仅仅是一个盾牌，并通过淬灭第二信使和-ROS来阻断宿主的促炎信号传导，以最大限度地减少宿主对细菌毒力的干扰。这意味着，这些细菌酶的联合靶向可以严重减弱葡萄球菌的毒力，同时增强宿主的免疫防御。 我们最近的毒力研究已经确定葡萄黄素作为一个重要的抗氧化剂产品上调期间S。金黄色葡萄球菌发病机制（Liu et al. JEM 2005）。在此基础上，我们的研究将利用分子科赫假设来研究另外两种S.金黄色葡萄球菌抗氧化剂、过氧化氢酶和烷基氢过氧化物还原酶C（AhpC）。在具体目标#1中，我们将定义过氧化氢酶和AhpC对S的贡献。金黄色葡萄球菌毒力的分子遗传学方法。在具体目标#2中，我们将评估葡萄球菌抗氧化剂是否调节吞噬细胞中的炎症信号或防止宿主操纵细菌毒力。在具体目标#3中，我们将探索针对这些抗氧化剂产品的表达或功能的治疗方法。意义：拟议的研究将解决有关S的基本问题。金黄色葡萄球菌-宿主相互作用，并发现新的治疗方法对治疗S。金黄色葡萄球菌病

DESCRIPTION (provided by applicant): Staphylococcus aureus is an important pathogen and a major public health concern both in hospital and community settings. A central determinant of health or disease during staphylococcal infection is the host and bacterial antioxidant and redox systems. The phagocyte oxidative burst defends the host by generating reactive oxygen species (ROS) that are directly toxic to invading microorganisms, but ROS also serve as second messengers in key inflammatory signaling networks, and interfere with S. aureus virulence upregulation. S. aureus opposes this strategy by inactivating ROS using specific antioxidants. In this proposal, we hypothesize that the bacterial antioxidants function more than just a shield, and act to block host pro-inflammatory signaling through quenching of second messengers, and-inactivate ROS to minimize host interference with bacterial virulence. By implication, combined targeting of these bacterial enzymes could severely attenuate Staphylococcal virulence while providing a boost to the host immune defense. Our recent virulence studies have identified staphyloxanthin as an important antioxidant product upregulated during S. aureus pathogenesis (Liu et al. JEM 2005). Extending on this theme, our proposed research will investigate using molecular Koch's postulate the virulence and antioxidant functions of two additional S. aureus antioxidants, catalase and alkyl hydroperoxide reductase C (AhpC). In Specific Aim #1, we will define the contribution of catalase and AhpC to S. aureus virulence using molecular genetic methods. In Specific Aim #2, we will assess whether staphylococcal antioxidants modulate inflammatory signaling in phagocytes or prevent host manipulation of bacterial virulence. In Specific Aim #3 we will explore therapeutic approaches that target expression or function of these antioxidant products. Significance: The proposed research will address fundamental questions about S. aureus-host interaction, and uncover novel therapeutic approaches toward treatment of S. aureus diseases.