Cellular Immunity Against Ehrlichia chaffeensis

描述（由申请人提供）：人类埃立克体病是由三种病原体引起的，包括沙菲埃立克体、嗜吞噬无原体和埃文伊氏杆菌。这些可能致命的感染对公共卫生构成严重威胁，特别是对免疫功能低下者和老年人。然而，对宿主的抗性机制和这些疾病出现的原因知之甚少。由于具有免疫功能的人类和小鼠感染沙非叶虫的过程相似，本项目拟用小鼠作为实验宿主，表征清除所需的宿主免疫反应，该模型将为人类应用提供数据。此外，广泛的分子、免疫学和遗传工具将使我们能够以其他物种不可能的方式操纵系统。具体来说，我们将测试三个假设：1)TH1型辅助性t细胞是清除沙菲赤霉素所必需的；2) t细胞分泌的细胞因子是宿主抵抗沙非伊虫感染的必要条件；3)巨噬细胞的激活有助于沙菲赤霉素的清除。几个观察结果构成了该项目的基础：免疫能力强的小鼠在16天内清除沙菲沙螨，这种清除与沙菲沙螨特异性TH1型IgG反应的表达、CTL反应和肉芽肿形成有关；在缺乏T细胞和b细胞的SCID小鼠中感染是致命的；缺乏功能性MHCII基因的小鼠在沙菲伊螨攻击后建立长期持续感染；巨噬细胞激活缺失小鼠发生短期持续性感染；预先激活ifn - γ可抑制沙菲棘球蚴的单核细胞感染。辅助t细胞、细胞毒性t细胞、b细胞反应、细胞因子和巨噬细胞活化的重要性将通过几种具有不同遗传背景的小鼠品系，并通过操纵其免疫系统来减少或增强特定的免疫成分来评估。使用细菌学、分子学、免疫学和病理学分析来监测感染，以评估宿主免疫和感染状态。该项目的长期目标是阐明宿主的免疫机制和病原体逃避策略，并最终利用这些信息制定有效的干预措施，以对抗沙菲沙螨和其他密切相关的生物。

DESCRIPTION (provided by applicant): Human ehrlichiosis is caused by three agents including Ehrlichia chaffeensis, Anaplasma phagocytophila and by E. ewengii. These potentially fatal infections pose a serious threat to public health, particularly to immunocompromised and elderly people. However, little is known about the mechanisms of host resistance and reasons for the emergence of these diseases. This project proposes to characterize the host immune response necessary for clearance using mouse as the experimental host because the course of E. chaffeensis infection is similar between immunocompetent humans and mice and the model will provide data for human applications. Moreover, the extensive array of molecular, immunological and genetic tools available for mice will allow us to manipulate the system in ways that are not possible in other species. Specifically, three hypotheses will be tested: 1)TH1 type helper T-cells are required for clearance of E. chaffeensis; 2) Secreted cytokines from T-cells are needed for host resistance to E. chaffeensis infections; 3) Macrophage activation contributes to the clearance of E. chaffeensis. Several observations form the basis for this project: immunocompetent mice clear E. chaffeensis by 16 days and the clearance is associated with the expression of an E. chaffeensis-specific TH1 type IgG response, CTL response and granuloma formation; the infections are fatal in SCID mice lacking T- and B-cells; mice lacking functional MHCII genes establish long-term persistent infections after E. chaffeensis challenge; mice deficient for macrophage activation develop short-term persistent infections; and prior activation with IFN-gamma inhibits monocyte infections with E. chaffeensis. The importance of helper T-cells, cytotoxic T-cells, B-cell responses, cytokines, and macrophage activation will be evaluated using several mouse strains with different genetic backgrounds and by manipulating their immune systems to diminish or enhance particular immune components. Infections will be monitored using bacteriological, molecular, immunological, and pathological analyses to assess host immunity and infection status. The long-term goals of this project are to elucidate host immune mechanisms, pathogen evasion strategies and to ultimately use the information to devise effective intervention measures against E. chaffeensis and other closely related organisms.