Vector-host-pathogen interface in monocytotropic ehrlichiosis

描述（由申请人提供）：埃利希体病是一种新出现的威胁生命的疾病，通过蜱在世界范围内的人类和动物中传播。虽然已经确定了针接种弥散性埃立克体病的全身免疫机制和免疫发病机制，但尚未对皮肤蜱传播部位和引流淋巴结的早期事件进行调查。媒介在病原体传播和宿主反应调节中的作用需要蜱传播的动物模型来确定感染的建立机制。在某些情况下，蜱虫唾液会引起细胞因子调节的失衡，并通过抑制抗原呈递、效应细胞迁移和杀微生物机制来抑制宿主的先天免疫和适应性免疫。这些对宿主反应的干扰为病原体建立感染创造了环境。本项目的长期目标是确定媒介-宿主-病原体相互作用在埃利希病毒感染建立中的作用以及埃利希病毒逃避宿主防御的机制。本应用程序的目的是表征蜱传播模型和确定免疫反应的早期事件对蜱传播的埃利希体。我们的中心假设是蜱虫唾液调节了局部宿主的免疫反应，促进了伊氏感染的建立。为了验证我们的假设，我们将：(1)描述单核细胞嗜性埃利希体病的媒介传播特征。工作假设：载体内的埃立克体的生命周期始于中肠，随后埃立克体迁移到唾液腺，在此期间细菌复制

DESCRIPTION (provided by applicant): Ehrlichioses are emerging life-threatening diseases transmitted by ticks in humans and animals worldwide. Although mechanisms of systemic immunity and immunopathogenesis to needle inoculated disseminated ehrlichiosis have been characterized, the early events in the cutaneous tick transmission site and draining lymph nodes have not been investigated. The role of the vector in pathogen transmission and modulation of the host response requires an animal model of tick transmission to determine the mechanisms of establishment of infection. Under some condition tick saliva causes an imbalance of cytokine regulation, and also suppresses host innate and adaptive immunity by inhibiting antigen presentation, effector cell migration, and microbicidal mechanisms. These disturbances of the host response create an environment for pathogens to establish infection. The long term goal of this project is to determine the role of the vector-host-pathogen interactions on the establishment of ehrlichial infection and the mechanisms of ehrlichial evasion of host defenses. The objective of this application is to characterize a tick transmission model and identify the early events of the immune response to the tick-transmitted ehrlichiae. Our central hypothesis is that tick saliva modulates the local host immune response facilitating establishment of ehrlichial infection. To test our hypothesis we will: (1) Characterize vector transmission of monocytotropic ehrlichiosis. Working hypothesis: The life cycle of ehrlichiae within the vector is initiated in th midgut followed by ehrlichial migration to the salivary glands, where the bacteria replicate during transmission; and (2) characterize the primary immune response to ehrlichial infection transmitted by tick feeding compared to needle inoculation. Working hypothesis: Establishment of ehrlichial infection is favored by modulation of innate immunity by tick saliva leading to ehrlichial entry into APCs (DCs and macrophages) and dissemination by evading the host defenses. We expect to understand the earliest events in the host immune response (innate immunity) and disease establishment in monocytotropic ehrlichiosis, as well as the host-vector-pathogen interface. PUBLIC HEALTH RELEVANCE: This project addresses an important issue regarding ehrlichioses, which are tick transmitted diseases, by study of the developmental cycle and migration of the pathogen within the vector during transmission and the events in the host skin. In thick-borne diseases the role of the vector on the establishment of infection has been studied for only a single pathogen, Borrelia, but no studies have been performed for other agents. This proposal will examine the migration dynamics and multiplication of ehrlichia in the tick organs during transmission and correlate these early events with the host innate immune response.