Francisella Infection in Ticks

描述(申请人提供)：图拉方济氏菌是图拉热症的病原体，图拉热症是一种由啮齿动物、大鼠及其体外寄生虫在环境中维持的人畜共患疾病。低感染剂量、与肺炎疾病相关的高死亡率以及通过基因工程改造图拉氏丝虫的可能性，促使人们加大努力，为治疗或疫苗确定关键靶点。已经为弗朗西塞氏菌开发了新的遗传方法和工具，使得在理解组织培养和动物模型系统中感染期间发生的一些生物学结果方面取得了快速进展。这项应用建议建立第一个扁虱感染的小鼠模型，并研究传播、组织定位和确定扁虱发育不同阶段细菌负荷的变化。两个实验室的技能都集中在这些主要目标上。Coburn博士带来了她在壁虱传播的疏螺旋体感染分析方面的经验，Frank博士为该项目贡献了她在A型和B型图拉氏菌的遗传学和发病机制方面的专业知识。壁虱传播的图拉氏丝虫是传播给人类的一种主要方式，但人们对这些节肢动物媒介中细菌的获取、维持或复制知之甚少。为了解决这一关键的知识差距，我们将建立第一个明确定义的壁虱-小鼠感染模型系统，使用非选择因子图拉氏丝虫株LVS。总体而言，我们建议填补我们对壁虱/F·图拉尔线虫生物学理解的一个重要空白，并为未来的工作铺平道路，使用遗传方法来识别介导壁虱维持和传播给哺乳动物宿主的细菌的重要成分。这些细菌成分可能成为治疗或疫苗干预的新靶点。

DESCRIPTION (provided by applicant): Francisella tularensis is the etiologic agent of tularemia, a zoonotic disease maintained in the environment by rodents, lagamorphs and their ectoparasites. The low infectious dose, the high mortality rate associated with pneumonic disease and the potential to genetically engineer F. tularensis have prompted increased efforts to identify critical targets for therapeutics or vaccines. New genetic approaches and tools have been developed for Francisella, allowing rapid progress in understanding some of the biological outcomes occurring during infections both in tissue culture and in animal model systems. This application proposes to develop the first tick-mouse model of Francisella infection and to study transmission, tissue localization and define the changes in bacterial burden during different stages of tick development. The skill sets of two laboratories are focused on these major goals. Dr. Coburn brings her experience in the analysis of tick-borne Borrelia infections and Dr. Frank contributes her expertise in the genetics and pathogenesis of types A and B F. tularensis to the project. Tick-borne F. tularensis is a major mode of transmission to humans, yet little is known about the acquisition, maintenance or replication of the bacteria in these arthropod vectors. To address this critical knowledge gap, we will establish the first well-defined tick-mouse infection model system using the non-select agent F. tularensis strain LVS. Overall, we propose to fill an important gap in our understanding of tick/F. tularensis biology and pave the way for future work using genetic approaches to identify important components of the bacterium that mediate maintenance in the tick and transmission to mammalian hosts. These bacterial components may serve as novel targets for therapeutic or vaccine interventions.