Vector-host-pathogen interface in monocytotropic ehrlichiosis

描述（由申请方提供）：埃立克体病是一种由蜱传播的威胁生命的疾病，在全球范围内传播给人类和动物。虽然全身免疫和免疫发病机制针接种播散性埃立克体病的特点，在皮肤蜱传播网站和引流淋巴结的早期事件尚未进行研究。媒介在病原体传播和调节宿主反应中的作用需要蜱虫传播的动物模型来确定感染建立的机制。在某些情况下，蜱唾液引起细胞因子调节的失衡，并且还通过抑制抗原呈递、效应细胞迁移和杀微生物机制来抑制宿主的先天性和获得性免疫。这些宿主反应的干扰为病原体建立感染创造了环境。本项目的长期目标是确定媒介-宿主-病原体相互作用在埃立克体感染建立中的作用以及埃立克体逃避宿主防御的机制。本申请的目的是表征蜱传播模型并识别对蜱传播的埃立克体的免疫应答的早期事件。我们的中心假设是，蜱唾液调节局部宿主免疫反应，促进埃立克体感染的建立。为了验证我们的假设，我们将：（1）描述单嗜性埃里希体病的媒介传播。工作假设：载体内埃里希体的生命周期始于中肠，随后埃里希体迁移到唾液腺，在唾液腺中细菌在体内复制。 传播;和（2）表征与针接种相比，对通过蜱饲养传播的埃立克体感染的初级免疫应答。工作假设：通过蜱唾液调节先天免疫，导致埃立克体进入APC（DC和巨噬细胞）并通过逃避宿主防御而传播，从而有利于埃立克体感染的建立。我们期望了解宿主免疫反应（先天免疫）和单核细胞埃立克体病疾病建立的最早期事件，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媒介内病原体的发育周期和迁移以及宿主皮肤中的事件，解决了关于埃立克体病（蜱传播疾病）的重要问题。在厚传播疾病中，仅针对单一病原体疏螺旋体研究了载体对建立感染的作用，但尚未针对其他病原体进行研究。本研究将探讨埃立克体在传播过程中在蜱器官中的迁移动力学和增殖，并将这些早期事件与宿主的先天免疫反应联系起来。

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.