BRUCELLA STATIONARY PHASE GENE EXPRESSION AND VIRULENCE

布鲁氏菌固定相基因表达和毒力

• 批准号: 6632434
• 负责人: ROY M ROOP
• 金额: $ 27.9万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-15 至 2004-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632434
• 关键词: Brucella abortus; DNA directed RNA polymerase; bacterial genetics; bacterial proteins; gene expression; host organism interaction; intracellular parasitism; laboratory mouse; macrophage; molecular cloning; virulence

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.

描述：布鲁氏菌属有几种致病特性， 用作生物战剂的严重潜在威胁， 生物恐怖主义具体来说，它们通过气溶胶途径具有高度传染性， 它们在人类中产生一种慢性的、使人衰弱的疾病， 治疗，目前还没有安全有效的疫苗来预防人类 布鲁氏菌病 延长宿主巨噬细胞的存活和复制是 关键的能力，以建立和维持慢性 感染宿主。在它们长期驻留在宿主巨噬细胞中期间， 布鲁氏菌会遇到各种恶劣的环境条件， 营养限制和暴露于活性氧中间体和酸性 实验证据表明，B.流产HFQ基因产物（也 称为宿主因子I或HF-I）对于这种能力至关重要。 生物体承受暴露于这些环境应力在主机 巨噬细胞 基于 有据可查的 功能 其肠 主要研究者的工作假设是B. 流产HFQ基因产物通过促进最佳的 编码固定相特异性的同源物的基因的翻译 RNA聚合酶σ因子RpoS。该项目的具体目标是：1） 克隆B。 流产rpoS基因，确认其与HF-I的调控联系，和 评价其对体外稳定期生理学的贡献， 在小鼠模型中的毒力; 2）确定HF-I和RpoS是否控制 B的固定相表达。 流产牛katE和sodC基因， 编码与小鼠毒力相关的重要主要抗氧化剂;以及3） 鉴定B中其他HF-1和Rpos调节基因。流产起关键作用 在这种细菌建立和维持慢性 感染 在小鼠宿主中。 定义患者的生理状态 细胞内布鲁氏菌病在慢性感染过程中的宿主和阐明 单个稳定期基因产物对成功的 在宿主巨噬细胞中存活和复制应该提供重要的基础 关于布鲁氏菌感染中宿主-病原体相互作用的信息。这 这些信息也可能有助于设计新的候选疫苗， 改进的化疗方法。