Spotted Fever Rickettesial Antigens

描述（由申请人提供）：本项目的长期目标是阐明斑点热群立克次体的保护性免疫机制。保护性免疫清除弥散性内皮感染机制的强大知识框架，通过静脉接种立克次体进入易感C3H小鼠，确定了我们知识中的一个重要空白，即初始感染事件。这一竞争性的更新应用提出通过皮内接种、立克次体与树突状细胞的相互作用、引流淋巴结中的T淋巴细胞启动、树突状细胞- nk细胞串音和血头蜱唾液的免疫调节作用等实验来缩小这一差距。初步结果表明，conorii可激活树突状细胞，影响感染结果。具体目的是：1)确定立克次体在体外和体内激活树突状细胞（dc）时对立克次体感染的遗传抗性或易感小鼠树突状细胞反应的差异，以及立克次体接种物中蜱虫唾液的存在对树突状细胞- dc相互作用的影响；2)确定立克次体激活dc在体内斑点热立克次体发病中的作用。包括对先天免疫和适应性免疫的影响，以及蜱虫唾液对立克次体免疫应答的影响。

DESCRIPTION (provided by applicant): The long-term goal of this project is the elucidation of the mechanisms of protective immunity against spotted fever group rickettsiae. A strong framework of knowledge of the mechanisms of protective immunity that clear disseminated endothelial infection established by intravenous inoculation of Rickettsia conorii into susceptible C3H mice has identified an important gap in our knowledge, namely of the initial infection events. This competing renewal application proposes to close that gap by experiments focused on intradermal inoculation, rickettsial interactions with dendritic cells, T lymphocyte priming in the draining lymph nodes, dendritic cell-NK cell cross talk, and immunomodulatory effects of Rhipicephalus sanguineus tick saliva. Preliminary results indicate that R. conorii activates dendritic cells, which influence the outcome of infection. The specific aims are 1) Determine the differences between the responses of dendritic cells of inbred mice genetically resistant or susceptible to Rickettsia conorii infection when the dendritic cells (DCs) are activated by the rickettsiae in vitro and in vivo and the effects of the presence of tick saliva in the rickettsial inoculum on the rickettsia-DC interaction and 2) Determine the role of activation of DCs by R. conorii on the pathogenesis of spotted fever rickettsiosis in vivo, including the effects on innate and adaptive immunity, and the effects of tick saliva in the rickettsial inoculum on the anti-rickettsial immune response. The experimental design takes advantage of well-established mouse models including one with complete innate resistance, one with dose-dependent mortality caused by R. conorii, and one employing R. australis that causes dose-dependent mortality in C57BL/6 mice enabling use of gene knockout approaches. In vitro studies, flow cytometry, real time PCR measurement of rickettsial load, immunohistochemistry, cytokine assays, ELISPOT assays, CTL assays, and other immunological approaches will be utilized in critically designed experiments to determine the effective generation of anti-rickettsial immunity.