A nonhuman primate model of Rickettsia prowazekii infection

普氏立克次体是流行性斑疹伤寒的病原体，这是一种媒介(虱子)传播的疾病。 以突然出现发烧症状为特征的，并有明显的病理后遗症。除了……之外 在恶劣和不卫生的环境中引起流行病的普罗瓦泽克杆菌也被确认为 具有生物武器的特征的。目前还没有疫苗可用来治疗 预防流行性斑疹伤寒，尽管目前正在开发新产品。一个完整的 确定免疫反应、安全性和保护性需要具有特征性的灵长类疾病模型 为预防普罗瓦泽克杆菌感染而开发的疫苗产品的有效性。这个项目的目标是 是为流行性斑疹伤寒开发一种健壮的非人类疾病模型，以加快对 新开发的疫苗产品。具体的假设是猕猴(Macaca)的使用 将为流行性斑疹伤寒的感染模型提供一个最佳的检测系统。 我们把这个假设建立在过去有限研究的观察基础上，这些研究详述了1)一个明确的剂量响应 先前的模型开发工作与使用恒河猴的Blinl品系的关系 当直接与实验感染无毒菌株进行比较时，以及2)典型的病理 一种播散性血管炎，包括中枢神经系统中的斑疹伤寒结节，模仿 人类临床综合征。基于这些观察，这项提议的实验重点是 恒河猴流行性斑疹伤寒模型的建立。 具体目标包括：1.)普氏罗氏杆菌静脉注射非人类灵长类动物模型的建立 感染。这将在未来的免疫和病理反应的背景下重新建立模型 涉及普罗瓦泽克杆菌感染的非人灵长类研究。2.)开发一个气溶胶挑战模式R。 Prowazekii挑战赛。普氏立克次体除了引起流行病外，还被认为是一种 生物威胁剂因其低剂量、气溶胶感染性和武器化历史而受到广泛关注。这个 气溶胶疾病模型将为测试专门开发的产品提供最佳系统 普罗瓦泽克乳杆菌对潜在粘膜攻击的保护作用。

Ricketisia prowazekii is the causative agent of epidemic typhus, a vector (louse)-borne disease characterized by a sudden onset of febrile symptoms with significant pathologic sequelae. In addition to causing epidemic disease in poor and unhygienic environments, R. prowazekii has also been identified as possessing the characteristics of a biological weapon. There presently is no vaccine available for protection against epidemic typhus, although development of new products is currently underway. A fully characterized primate model of disease is needed to determine immune response, safety, and protective efficacy of vaccine products developed to protect against R. prowazekii infection. The goal of this project is to develop a robust nonhuman model of disease for epidemic typhus in order to accelerate testing of newly developed vaccine products. The specific hypothesis is that use of the Rhesus macaque (Macaca mulatta) of Chinese origin will provide an optimal test system for an infection model of epidemic typhus. We base this hypothesis upon the observations from limited past studies that detailed 1) a clear doseresponse relationship in prior model development efforts with the Breinl strain using Rhesus macaques when directly compared to experimental infection with avirulent strains, and 2) typical pathology in the form of disseminated vasculitis including typhus nodules in the central nervous system that emulated the human clinical syndrome. Based on these observations, the experimental focus of this proposal is on the model development of epidemic typhus in the Rhesus macaque. Specific aims include: 1.) Reestablish a nonhuman primate model for intravenous R. prowazekii infection. This will reestablish the model in the context of immune and pathologic response for future nonhuman primate studies involving R. prowazekii infection. 2.) Develop an aerosol challenge model R. prowazekii challenge. Rickettsia prowazekii, in addition to causing epidemic disease, is considered a biological threat agent because of its low dose, aerosol infectivity and history of weaponization. The aerosol disease model will provide an optimal system for testing of products developed expressly for protective efficacy against potential mucosal challenge with R. prowazekii.