Pathogen-host-vector interactions in a Rickettsia-guinea pig-tick model

项目摘要/摘要 在美国，斑点热立克次体病的诊断结果从良好到 戒备森严，取决于致病因素和相关疾病。属于壁虱传播的斑点热组 在美国引起疾病的立克次体(SFGR)，落基山斑点热病的病原体里氏立克次体 (RMSF)，是致病性最强的。另一种在美国的致病性SFGR，帕氏立克次体，被证实 差不多15年前。帕氏立克次体立克次体病在范围上与RMSF重叠，导致病情较轻 疾病。位于美国西部的364D立克次体现在是第三种与人类疾病有关的壁虱传播的SFGR。 在美国，硬蜱(硬蜱)中剩余的SFGR被认为是非致病的、未知的或潜在的 致病性。暴露在不被认为是致病的SFGR中刺激免疫的程度 致病性SFGR对感染或临床疾病的影响尚不清楚。我们对主持人的理解 免疫力将受益于利用扁虱的扁虱-SFGR-脊椎动物宿主传播模型的研究 已知携带致病性和非致病性SFGR的载体和已知的动物模型 临床立克次体病。在这里，我们使用斑点钝线虫(墨西哥湾沿岸扁虱)及其相关立克次体R. Parkeri，一种可在生物安全二级水平下研究的致病性SFGR，“Candidatus Rickettsia andeanae”，a 可传播但被认为非致病的SFGR，以及豚鼠模型。此外，在这个项目中， 我们解决了在区分地理范围重叠的致病性SFGR抗体方面的挑战。 我们的长期目标是评估脊椎动物宿主免疫在应对SFGR感染中的作用。我们的整体 此Cobre第二阶段项目的目标是阐明SFGR暴露后初级免疫系统的贡献 通过滴答声传输。具体地说，我们将确定先前接触SFGR对感染和临床的影响 用豚鼠模型研究致病性SFGR的致病机制。此外，我们还将测试立克次体的效用 诊断分析中的物种特异性抗原。我们的中心假设是R. Parkeri感染是由缺乏有效的先天免疫反应和缺乏 对先前SFGR暴露的适应性反应。我们的理由是先天免疫力，第一道防线 硬蜱传播的疾病，不足以防止巴氏杆菌感染硬蜱近端的内皮细胞。 咬一口。我们在暴露于“念珠菌立克次体”的动物中检测到了对SFGR的抗体反应。 在斑点拟青霉中也发现了非致病性的SFGR，并认为这可能会阻止和 脊椎动物中由致病的帕克氏杆菌引起的疾病。我们提出的研究具有重要意义，因为它将 洞察先前接触SFGR对疾病发展的贡献，从而了解斑点的风险 热立克次体病。我们相信，这是创新的，结合了现有的专业知识在一个斑点-SFGR 系统和最近在免疫学方面的额外专业知识，以创建解决免疫保护的协同效应 以及需要使用血清学检测来具体区分斑点热立克次体病的病原体。

PROJECT SUMMARY/ABSTRACT In the United States (US), diagnosis of spotted fever rickettsiosis leads to a prognosis ranging from good to guarded, depending on the causative agent and associated disease. Of the tick-borne spotted fever group Rickettsia (SFGR) that cause disease in the US, Rickettsia rickettsii, the agent of Rocky Mountain spotted fever (RMSF), is the most pathogenic. A second pathogenic SFGR in the US, Rickettsia parkeri, was confirmed over nearly 15 years ago. Rickettsia parkeri rickettsiosis, which overlaps in range with RMSF, results in milder disease. Rickettsia 364D, in the western US, is now the third tick-borne SFGR associated with human disease. The remaining SFGR in hard ticks (Ixodidae) in the US are considered non-pathogenic or of unknown or potential pathogenicity. The extent to which exposure to SFGR that are not considered pathogenic stimulates an immune response that affects infection or clinical disease from pathogenic SFGR is unclear. Our understanding of host immunity would benefit from studies using an tick-SFGR-vertebrate host transmission model that exploits a tick vector known to harbor both a pathogenic and non-pathogenic SFGR and animal model known to demonstrate clinical rickettsiosis. Here, we use Amblyomma maculatum (Gulf Coast tick), and its associated rickettsiae, R. parkeri, a pathogenic SFGR that can be studied under biosafety level two, “Candidatus Rickettsia andeanae”, a SFGR that is transmissible but considered non-pathogenic, and a guinea pig model. Additionally in this project, we address challenges in distinguishing antibodies to the pathogenic SFGR that overlap in geographical range. Our long-term goal is to evaluate the role of vertebrate host immunity in response to SFGR infection. Our overall objective in this COBRE Phase II project is to clarify primary immune system contributions after SFGR exposure via tick transmission. Specifically, we will determine how prior SFGR exposure influences infection and clinical disease from the pathogenic SFGR using a guinea pig model. Additionally, we will test the utility of Rickettsia species-specific antigens in a diagnostic assay. Our central hypothesis is that successful establishment of R. parkeri infection is determined by both the lack of an effective innate immune response and the lack of an adaptive response to prior SFGR exposure. Our rationale is that innate immunity, the first line of defense against tick transmitted disease, is not sufficient to prevent R. parkeri infection of endothelial cells proximal to the tick bite. We have detected an antibody response to SFGR in animals exposed to “Candidatus Rickettsia andeanae,” the non-pathogenic SFGR also found in A. maculatum, and believe this may prevent establishment of and disease by the pathogenic SFGR, R. parkeri, in vertebrates. Our proposed research is significant because it will provide insight into the contributions of prior SFGR exposure to development of disease, and thus risk of spotted fever rickettsiosis. We believe this is innovative by combining existing expertise in the A. maculatum-SFGR system and recent additional expertise in immunology to create a synergy that addresses immune protection and the need to specifically distinguish causative agents of spotted fever rickettsiosis using serologic assays.