Vector-host-pathogen interface in monocytotropic ehrlichiosis

描述（由申请人提供）：埃利希体病是新出现的危及生命的疾病，由蜱虫在全世界人类和动物中传播。尽管针头接种播散性埃利希体病的全身免疫和免疫发病机制已得到表征，但皮肤蜱传播部位和引流淋巴结的早期事件尚未得到研究。载体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建立的机制。在某些情况下，蜱唾液会导致细胞因子调节失衡，并通过抑制抗原呈递、效应细胞迁移和杀菌机制来抑制宿主先天性和适应性免疫。这些宿主反应的干扰为病原体建立感染创造了环境。该项目的长期目标是确定载体-宿主-病原体相互作用对埃利希体感染建立的作用以及埃利希体逃避宿主防御的机制。本应用的目的是描述蜱传播模型的特征，并确定对蜱传播的埃利希亚科免疫反应的早期事件。我们的中心假设是蜱唾液调节局部宿主免疫反应，促进埃利希体感染的建立。为了检验我们的假设，我们将：（1）描述单核埃利希体病的载体传播特征。工作假设：载体内埃利希体的生命周期始于中肠，然后埃利希体迁移到唾液腺，细菌在唾液腺中复制 传输； (2) 与针头接种相比，表征对蜱虫喂养传播的埃利希体感染的主要免疫反应。工作假设：蜱唾液对先天免疫的调节有利于埃利希体感染的建立，导致埃利希体进入 APC（树突状细胞和巨噬细胞）并通过逃避宿主防御进行传播。我们期望了解单核埃利希体病的宿主免疫反应（先天免疫）和疾病建立的最早事件，以及宿主-载体-病原体界面。 公共卫生相关性：该项目通过研究传播过程中病原体在媒介内的发育周期和迁移以及宿主皮肤中的事件，解决了有关埃利希体病（蜱传播疾病）的重要问题。在厚传疾病中，仅针对单一病原体疏螺旋体对载体在感染建立中的作用进行了研究，但尚未对其他病原体进行研究。该提案将检查传播过程中埃利希体在蜱器官中的迁移动态和增殖，并将这些早期事件与宿主先天免疫反应相关联。

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.