An Inhalation Model of Q Fever in Guinea Pigs

描述(申请人提供)：Q热是一种具有世界性意义的人畜共患病，由伯氏柯克斯体细胞内专性细菌引起。由于伯氏梭菌的高度传染性，它通过气溶胶感染的正常途径，以及它在恶劣环境条件下的耐受性，该生物已被列入可能用于生物恐怖主义和生物战的制剂名单。用于研究这种疾病的动物模型包括通过腹腔接种感染的小鼠和豚鼠。很少有研究利用气雾剂感染，也没有研究评估吸入剂量对临床疾病的影响。对Q热在豚鼠体内的免疫反应的描述是不完整的，该模型在疫苗测试中的应用尚未见报道。 这项研究的具体目的是：1)建立Q热豚鼠模型的气溶胶感染途径，2)表征气溶胶感染豚鼠的免疫反应，3)确定重组蛋白所产生的保护性免疫的性质。豚鼠将在一个专门的小室中感染多剂量的布氏梭菌，该小室旨在将液滴核直接输送到肺泡腔。每只动物的临床体征、病理变化和对感染的免疫反应将被评估并与剂量相关。基于这些结果的单一致病剂量将用于疫苗挑战研究。这些研究的结果对于实现为有感染伯氏梭菌风险的个人开发安全、有效的亚单位疫苗这一长期目标至关重要。 拟议中的工作将提供有关这一未得到充分利用的模型的重要信息，供当前和未来的疫苗开发研究使用，并将使罗素博士有机会作为一名独立研究员发展她的科学生涯。

DESCRIPTION (provided by applicant): Q fever is a zoonotic disease of worldwide significance caused by the obligate intracellular bacterium Coxiella burnetii. Due to the highly infectious nature of C. burnetii, its normal route of infection by aerosol, and its hardiness in adverse environmental conditions, the organism has been included in the list likely agents to be used in bioterrorism and biological warfare. Animal models being used to study this disease include mice and guinea pigs infected through intraperitoneal inoculation. Few studies have utilized aerosol infection, and none have evaluated the effect of inhalation dose on clinical disease. Descriptions of the immune response in guinea pigs to Q fever are incomplete, and application of this model for vaccine testing has not been reported. The specific aims for the proposed studies are: 1) Establish the aerosol route of infection in the guinea pig model of Q fever, 2) Characterize the immune response in aerosol-infected guinea pigs, and 3) Determine the nature of protective immunity conferred by recombinant proteins. Guinea pigs will be infected with multiple doses of C.burnetii in a specialized chamber designed to deliver droplet nuclei directly to the alveolar spaces. Each animal's clinical signs, pathologic changes, and immunologic response to infection will be evaluated and correlated with dose. A single disease-causing dose based on these results will be used in vaccine challenge studies. The findings of these studies are of utmost importance in reaching the long-range goal of the development of a safe, effective subunit vaccine for individuals at risk of infection with C. burnetii. The proposed work will provide vital information about this underutilized model for use in current and future vaccine development studies and will allow Dr. Russell the opportunity to develop her scientific career as an independent investigator.