Perpetuation of Francisella tularensis

土拉弗朗西斯菌的永存

• 批准号: 7036059
• 负责人: Sam R Telford
• 金额: $ 39.29万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7036059
• 关键词: epizootiology; pathology; ticks

DESCRIPTION (provided by applicant): Francisella tularensis is the causative agent of tularemia, an acute febrile infection with variable presentation and outcomes. Although the agent is said to be maintained in nature by cycles involving ticks and rodents or rabbits, its great infectivity and presumptive environmental stability suggests other modes of perpetuation. Our longterm goal is to determine the proximal determinants of risk for outbreaks of tularemia, and in particular, how the agent is maintained between epizootics. The specific hypothesis is that multiple modes of transmission are facilitated by a metapopulation structure of genetic variants within an enzootic focus; certain variants may be better adapted to ticks as opposed to environmental reservoirs. We base our hypothesis on our investigation of the ongoing pneumonic tularemia outbreak on Martha's Vineyard, wherein we have found (1) that 11 F. tularensis variants circulate in our island study sites; and (2) that certain of these variants appear to be associated solely with ticks or with animals. Based on these observations, we now seek to determine experimentally whether certain variants are more likely to be inherited by ticks, remain stable within the environment, or cause pulmonary pathology. The specific aims, therefore, are to: 1. Determine whether variants differ in their capacity to be transmitted by ticks, including maintenance by inheritance. We will clone strains from the multiple loci variable number tandem repeat analysis (MLVA)-defined genotypes, and measure the vector competence of various ticks for such clones. 2. Determine whether variants differ in their capacity to stably persist in the environment, including resistance to dessication, survival in water, and colonisation of freeliving or parasitic cyst-forming protozoa. We will measure the viability and survival of each genotype under simulated environmental stresses in vitro. 3. Determine whether variants differ in their infectivity to and virulence within rodents, including capacity to induce pulmonary pathology or hematogenously disseminate. Rats and mice will be infected by intratracheal instillation, as well as parenteral delivery, and tissues examined by histopathology, immunohistochemistry, PCR, cultivation, and cytokine mRNA expression. Taken together, these observations will provide a basis for understanding how the agent of tularemia is perpetuated on Martha's Vineyard, and why pneumonic human disease is prevalent there.

描述（由申请人提供）：Francisella tularensis是Tularemia的病因，Tularemia是一种急性发热感染，具有可变的表现和结果。尽管据说该代理在自然界中通过涉及壁虱和啮齿动物或兔子的周期来维持，但其巨大的感染性和推定的环境稳定性表明了其他永久性的​​模式。我们的长期目标是确定暴发爆发风险的近端决定因素，尤其是在epizootics之间如何保持代理。具体的假设是，多种传播模式是通过在enzootic Focus中的遗传变异结构促进的。某些变体可以更好地适应tick虫，而不是环境库。我们基于对玛莎葡萄园正在进行的肺炎爆发爆发的研究，我们发现（1）在我们的岛屿研究地点发现了11f。tularensis变体在我们的岛屿研究地点循环； （2）某些这些变体似乎仅与壁虱或动物相关。基于这些观察结果，我们现在试图通过实验确定某些变体是否更有可能被tick遗传，在环境中保持稳定或引起肺病理。因此，特定的目的是：1。确定变体在其被tick传输的能力上是否有所不同，包括通过继承维护。我们将从多个基因座变量串联重复分析（MLVA）定义的基因型中克隆菌株，并测量此类克隆的各种刻度的矢量能力。 2。确定变异的能力在环境中稳定持续存在的能力是否有所不同，包括抗性，水中的存活以及自由式囊肿或寄生虫形成原生动物的定殖。我们将在体外模拟环境应力下测量每种基因型的生存力和存活。 3。确定变异的感染性和啮齿动物内的毒力是否有所不同，包括诱导肺病理或血源性传播的能力。大鼠和小鼠将通过气管内滴注以及肠胃外的分娩以及通过组织病理学，免疫组织化学，PCR，培养和细胞因子mRNA表达感染。综上所述，这些观察结果将为理解玛莎葡萄园的tular症毒剂如何持续，以及为什么肺炎人类疾病在那里普遍存在。