A NONHUMAN PRIMATE MODEL OF RICKETTSIA PROWAZEKII INFECTION (EPIDEMIC TYPHUS)

普瓦泽克立克次体感染（流行性斑疹伤寒）的非人类灵长类动物模型

• 批准号: 7958705
• 负责人: CHAD J. ROY
• 金额: $ 5.8万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958705
• 关键词: Accounting; Aerosols; Animals; Arts; Biological; Characteristics; Chinese People; Clinical; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Disease model; Dose; Environment; Epidemic; Fever; Funding; Future; Goals; Grant; Human; Immune; Immune response; Immunologics; Infection; Injection of therapeutic agent; Institution; Intravenous; Lice; Macaca mulatta; Measurement; Methodology; Modeling; Neuraxis; Nodule; Pathologic; Pathology; Physiological; Primates; Recording of previous events; Reporting; Research; Research Personnel; Resources; Rickettsia prowazekii; Safety; Schedule; Source; Symptoms; Syndrome; System; Testing; Typhus; United States National Institutes of Health; Vaccines; Vasculitis; base; falls; model development; new product development; nonhuman primate; protective efficacy; response; vector; weapons

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rickettsia 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 dose-response 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. The specific aims are to: 1. Reestablish a nonhuman primate model for intravenous R. prowazekii infection. Studies over 25 years ago reported on model development of R. prowazekii infection in the nonhuman primate without the benefit of advances in immunologic and physiologic measurement. We will utilize the state of the art methodology during experimental infection to achieve precise account of biological response in infected animals. 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. As such, new products must provide protective efficacy against a realistic aerosol challenge. Clinical and immunologic parameters obtained from the IV Rickettsia prowazekii infections will serve as a guide to development of the aerosol model of disease. 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. To date, six (6) rhesus macaques have been exposed to R. prowazekii by IV injection within biocontainment. Aerosol challenges of the remaining animals on this effort are scheduled for fall 2009.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 普氏立克次体是流行性斑疹伤寒的病原体，斑疹伤寒是一种媒介(虱子)传播的疾病，其特征是突然出现发热症状，并有显著的病理后遗症。除了在恶劣和不卫生的环境中引起流行病外，普罗瓦泽克杆菌还被确认具有生物武器的特征。尽管目前正在开发新产品，但目前还没有预防流行性斑疹伤寒的疫苗。需要一个完全表征疾病的灵长类动物模型来确定免疫反应、安全性和疫苗产品的保护效力，以防止普罗瓦泽克杆菌感染。该项目的目标是开发一种针对流行性斑疹伤寒的强大的非人类疾病模型，以加快对新开发的疫苗产品的测试。具体的假设是，使用起源于中国的恒河猴(Macaca Mulatta)将为流行性斑疹伤寒的感染模型提供一个最佳的测试系统。我们基于对过去有限研究的观察，这些研究详细说明了1)在使用恒河猴与实验感染无毒菌株进行直接比较时，先前使用恒河猴进行的Blinl株模型开发工作中明确的剂量-反应关系，以及2)典型的病理形式，包括模仿人类临床综合征的中枢神经系统中的斑疹伤寒结节。基于这些观察，这项建议的实验重点是在恒河猴中建立流行性斑疹伤寒的模型。具体目的是：1.建立普氏弧菌静脉感染的非人灵长类动物模型。25年前的研究报告了在非人类灵长类动物中普氏弧菌感染的模型发展，但没有受益于免疫学和生理测量的进步。我们将在实验感染过程中利用最先进的方法学来实现对受感染动物的生物反应的精确描述。这将在免疫和病理反应的背景下重新建立模型，用于未来涉及普罗瓦泽克杆菌感染的非人类灵长类动物研究。2.开发气溶胶挑战模型R.prowazekii挑战。普氏立克次体除了引起流行病外，还因其低剂量、气溶胶传染性和武器化历史而被认为是一种生物威胁因子。因此，新产品必须针对现实的气雾剂挑战提供保护效果。从普氏立克次体感染中获得的临床和免疫学参数将作为发展疾病气雾剂模型的指南。气溶胶疾病模型将为测试专门为抵御普罗瓦泽克杆菌潜在的粘膜挑战而开发的产品提供一个最佳系统。到目前为止，已经有六(6)只恒河猴通过静脉注射生物围栏内的普罗瓦泽克杆菌而暴露于该病毒。其余动物在这一努力中面临的气溶胶挑战定于2009年秋季进行。