Vector-host-pathogen interface in monocytotropic ehrlichiosis

描述(申请者提供)：埃立克斯病是一种新出现的威胁生命的疾病，由扁虱在世界各地的人和动物中传播。尽管针刺接种播散性埃立克体病的系统免疫和免疫致病机制已有研究，但在皮肤硬蜱传播部位和引流淋巴结的早期事件尚未被研究。媒介在病原体传播和调节宿主反应中的作用需要一种动物模型来确定感染的机制。在某些情况下，扁虱唾液会引起细胞因子调节的失衡，并通过抑制抗原提呈、效应细胞迁移和杀菌机制来抑制宿主的先天免疫和获得性免疫。宿主反应的这些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病媒-宿主-病原体相互作用在埃利希感染的建立中的作用以及埃利希逃避宿主防御的机制。该应用程序的目的是描述壁虱传播模型，并确定对壁虱传播的埃立克体的免疫反应的早期事件。我们的中心假设是扁虱唾液调节局部宿主免疫反应，促进埃立克病毒感染的建立。为了验证我们的假设，我们将：(1)描述单核细胞增生性埃立克体病的媒介传播。工作假设：埃利希菌在载体内的生命周期在中肠开始，随后埃利希菌迁移到唾液腺，在那里细菌在 传播；以及(2)与针头接种相比，描述了通过扁虱饲养传播的埃立克病毒感染的主要免疫反应。工作假说：扁虱唾液调节先天免疫，导致埃立克进入APC(DC和巨噬细胞)并通过逃避宿主防御而传播，有利于埃立克感染的建立。我们期望了解单核细胞增生性埃立克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-病媒-病原体的界面。 公共卫生相关性：该项目通过研究病原体在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，解决了埃立克斯病的一个重要问题，埃立克斯病是硬蜱传播的疾病。在厚传疾病中，只对一种病原体--疏螺旋体进行了媒介在建立感染中的作用的研究，但没有对其他病原体进行研究。这项建议将研究埃立克体在传播过程中在扁虱器官中的迁移动态和繁殖，并将这些早期事件与宿主的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.