BRUCELLA STATIONARY PHASE GENE EXPRESSION AND VIRULENCE

描述：布鲁氏菌属。有几种致病特性，使它们成为 用作生物战和生物战毒剂的严重潜在威胁 生物恐怖主义。具体地说，它们通过气溶胶路线具有很高的传染性， 它们会在人类身上产生一种慢性的、令人衰弱的疾病，很难 治疗，目前还没有安全有效的疫苗来预防人类 布鲁氏菌病。在宿主巨噬细胞中延长存活和复制 对布鲁氏菌建立和维持慢性感染的能力至关重要 宿主中的感染。在它们长期驻留在宿主巨噬细胞期间， 布鲁氏菌会遇到各种恶劣的环境条件，包括 营养限制和接触活性氧中间体和酸性 PH值。实验证据表明，流产杆菌Hfq基因产物(也 称为主机因子I，或HF-I)对于此容量是必不可少的 在寄主体内承受这些环境压力的有机体 巨噬细胞。基于对其肠道功能的充分研究 与之对应，首席调查员的工作假设是B。 流产的Hfq基因产物通过促进最佳 翻译编码固定相特异性同系物的基因 RNA聚合酶西格玛因子rpos。该项目的具体目标是：1) 克隆流产杆菌rpos基因，确认其与HF-I的调控联系，以及 评价其对体外静止期生理学的贡献 小鼠模型的毒力；2)确定HF-I和rpos是否控制 流产乳杆菌KATE和SODC基因的稳定期表达 编码与小鼠毒力有关的重要主要抗氧化剂；以及3) 确定流产杆菌中其他受HF-I和rpos调控的关键基因 在这种细菌建立和维持慢性疾病的能力中的作用 小鼠宿主的感染。定义人的生理状态 宿主慢性感染过程中的胞内布鲁氏菌及其鉴定 单个固定相基因产物对成功的贡献 宿主巨噬细胞的存活和复制应提供重要的基础 关于布鲁氏菌感染中宿主与病原体相互作用的信息。这 信息也可能有助于设计新的候选疫苗和 改进化疗方法。

DESCRIPTION: Brucella spp. have several pathogenic properties that make them a serious potential threat for use as agents of biological warfare and bioterrorism. Specifically, they are highly infectious by the aerosol route, they produce a chronic, debilitating disease in humans that is difficult to treat, and there is no safe and effective vaccine available to prevent human brucellosis. Prolonged survival and replication in host macrophages is critical to the capacity of the brucellae to establish and maintain chronic infection in the host. During their long term residence in host macrophages, the brucellae encounter a variety of harsh environmental conditions including nutrient limitation and exposure to reactive oxygen intermediates and acidic pH. Experimental evidence indicates that the B. abortus hfq gene product (also known as host factor I, or HF-I) is essential for the capacity of this organism to withstand exposure to these environmental stresses in host macrophages. Based on the well documented function of its enteric counterparts, the Principal Investigator's working hypothesis is that the B. abortus hfq gene product performs this function by facilitating optimal translation of the gene encoding a homologue of the stationary phase specific RNA polymerase sigma factor RpoS. The specific aims of this project are: 1) to clone the B. abortus rpoS gene, confirm its regulatory link to HF-I, and evaluate its contribution to stationary phase physiology in vitro and virulence in the mouse model; 2) to determine if HF-I and RpoS control stationary phase expression of the B. abortus katE and sodC genes, which encode important primary antioxidants linked to virulence in mice; and 3) to identify other HF-I and RpoS-regulated genes in B. abortus that play critical roles in the capacity of this bacterium to establish and maintain chronic infection in the murine host. Defining the physiologic state of the intracellular brucellae during chronic infection in the host and elucidating the contributions of individual stationary phase gene products to successful survival and replication in host macrophages should provide important basic information regarding host-pathogen interactions in Brucella infections. This information may also be useful for the design of novel vaccine candidates and improved chemotherapeutic approaches.