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

立克次体-豚鼠-蜱模型中病原体-宿主-载体相互作用

• 批准号: 10004099
• 负责人: Andrea Soares Varela-Stokes
• 金额: $ 31.03万
• 依托单位: MISSISSIPPI STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004099
• 关键词: Address; Affect; Amblyomma; Amino Acids; Animal Model; Animals; Antibodies; Antibody Response; Antigens; Arbovirus Infections; B-Lymphocytes; Biological Assay; Bite; Boutonneuse Fever; Cavia; Cells; Cellular Immunity; Centers of Research Excellence; Clinical; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dermacentor; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epidemiology; Exposure to; GTP-Binding Protein alpha Subunits, Gs; Geography; Goals; Health; Human; Immune; Immune response; Immune system; Immunity; Immunology; Infection; Innate Immune Response; Interferon Type II; Ixodidae; Knowledge; Membrane Proteins; Mission; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Natural Immunity; Natural Killer Cells; Outcome; Outcomes Research; Pathogenicity; Peptide antibodies; Peptides; Phase; Population; Proteins; Public Health; Research; Rickettsia; Rickettsia Infections; Rickettsia akari; Rickettsia conorii; Rickettsia parkeri; Rickettsia rickettsii; Rickettsialpox; Risk; Rocky Mountain Spotted Fever; Role; Serology; Severities; Symptoms; System; T cell response; T-Lymphocyte; TNF gene; Testing; Ticks; United States; United States National Institutes of Health; Vertebrates; Virulent; adaptive immune response; base; clinically relevant; diagnostic assay; disease transmission; disorder risk; exposed human population; fitness; gulf coast; human disease; immunological status; indexing; infection rate; innovation; insight; mortality; novel diagnostics; outcome forecast; pathogen; polyclonal antibody; prevent; response; spotted fever; synergism; tick bite; tick feeding; tick-borne; tool; transmission process; vector; vector tick; vector transmission

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.

项目总结/摘要 在美国，斑点热立克次体病的诊断导致从良好到严重的预后。 根据病原体和相关疾病的不同，蜱传斑疹热的一部分 立克次氏体（SFGR），在美国引起疾病，立克次氏体，落基山斑疹热的代理人 （RMSF），是最致病的。在美国，第二种致病性SFGR，即帕克氏立克次体，已被证实为 差不多15年前。与RMSF在范围上重叠的帕氏立克次体立克次体病， 疾病美国西部的立克次体364 D是第三种与人类疾病相关的蜱传SFGR。 在美国，硬蜱（硬蜱科）中的其余SFGR被认为是非致病性的或未知的或潜在的 致病性暴露于不被认为具有致病性的SFGR刺激免疫的程度 影响致病性SFGR感染或临床疾病的反应尚不清楚。我们对主机的理解 免疫力将受益于使用蜱-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的载体和已知证明 临床立克次体病在这里，我们使用斑点钝眼蜱（墨西哥湾海岸蜱），及其相关的立克次体，R。 parkeri，一种致病性SFGR，可以在生物安全二级下进行研究，“安氏立克次体”， SFGR是可传播的，但被认为是非致病性的，和豚鼠模型。此外，在这个项目中， 我们解决了区分在地理范围上重叠的致病性SFGR的抗体的挑战。 我们的长期目标是评估脊椎动物宿主免疫应答SFGR感染的作用。我们的整体 本COBRE第二阶段项目的目标是阐明SFGR暴露后主要免疫系统的作用 通过蜱虫传播。具体来说，我们将确定之前的SFGR暴露如何影响感染和临床 疾病的致病性SFGR使用豚鼠模型。此外，我们将测试立克次体的效用 种特异性抗原在诊断测定中的应用。我们的中心假设是R. 帕克氏菌感染是由缺乏有效的先天免疫应答和缺乏有效的免疫应答决定的。 对先前SFGR暴露的适应性反应。我们的理论基础是先天免疫系统， 蜱传播疾病，不足以防止R。蜱近端内皮细胞的帕克氏感染 咬人的我们已经检测到暴露于“安氏立克次体”的动物对SFGR的抗体应答， 非致病性SFGR也存在于A.斑点，并认为这可能会阻止建立和 病的病原SFGR，R. parkeri，在脊椎动物中。我们提出的研究是重要的，因为它将 提供了对先前SFGR暴露对疾病发展的贡献的深入了解， 发热性立克次体病我们相信，这是创新的结合现有的专业知识，在A。斑-SFGR 系统和最近在免疫学方面的其他专业知识，以创造一种解决免疫保护问题的协同作用 以及需要使用血清学测定来特异性区分斑点热立克次体病的病原体。