Granulocytic Ehrlichiosis: Cell-Pathogen Interactions

描述(申请人提供)：人类粒细胞性埃立克体病(HGE)是一种由专性细胞内细菌引起的新出现的、潜在致命的人畜共患病。尽管以前的HGE病原体无浆体吞噬细胞病主要在粒细胞内生活和复制，但多发性红细胞减少症，特别是血小板减少症，是感染的一贯特征。吞噬假单胞菌与中性粒细胞和血小板在体内的相互作用以及这些相互作用对感染效率、细胞减少、病原体分布和传播的影响尚不清楚。本项目的目标是利用HGE小鼠模型和体外细胞技术，根据血液学异常和体内感染动力学了解病原体与宿主细胞的相互作用。研究的目标是首先确定白细胞和血小板与吞噬阿司匹林的相互作用和对其的反应，其次确定这些相互作用在决定病原体分布和传播中所起的作用。根据初步数据，这项研究的中心假设是，在感染早期，吞噬细胞嗜血杆菌附着并激活粒细胞和血小板，导致细胞黏附和分布的改变，从而直接影响细胞-病原体的运输，促进病原体的复制和传播。拟议的工作重点是一种新出现的、具有潜在严重血液学改变的人畜共患疾病。这项工作的重大积极影响将包括加强对体内细菌致病机制的理解，以及阐明可能的靶标来阻断从动物宿主到扁虱载体的传播循环。拟议的临床科学家发展导师奖(KO8)的目的是为候选人提供过渡到独立学术临床医生兼科学家的职位所需的指导和资源。该奖项非常适合已完成专业兽医学位、临床病理学培训和比较病理学博士学位但尚未完成博士后研究培训的候选人。目前，应聘者是一家实力雄厚的研究机构的初级教员，具有明确的使命和追求独立研究计划的愿望。

DESCRIPTION (provided by applicant): Human granulocytic ehrlichiosis (HGE) is an emerging, potentially fatal, tick-borne zoonotic disease caused by an obligate intracellular bacterium. Although Anaplasma phagocytophila, formerly the HGE agent, lives and replicates primarily within granulocytes, multiple cytopenias, especially thrombocytopenia, are a consistent hallmark of infection. The interaction of A. phagocytophila with neutrophils and platelets in vivo and the manner in which these interactions contribute to infection efficiency, cytopenias, pathogen distribution and transmission are still unclear. The goal of this project is to understand pathogen interaction with host cells in light of hematologic abnormalities and in vivo infection kinetics utilizing a murine model of HGE and in vitro cell techniques. Study objectives are first, to determine leukocyte and platelet interaction with, and response to, A. phagocytophila and, second, to determine the role, if any, these interactions play in determining pathogen distribution and transmission. The central hypothesis for the proposed research, based on preliminary data, is that during early infection, A. phagocytophila adheres to and activates both granulocytes and platelets resulting in alterations in cell adhesion and distribution that directly affect cell-pathogen trafficking and facilitate pathogen replication and transmission. The proposed work is focused on an emerging, zoonotic disease with potentially serious hematologic alterations. Significant positive impacts of this work will include enhanced understanding of in vivo bacterial pathogenesis as well as elucidation of possible targets for interruption of the transmission cycle from animal host to tick vector. The purpose of the proposed Mentored Clinical Scientist Development (KO8) award is to provide the candidate with the mentoring and resources needed for transition into the position of an independent academic clinician-scientist. The award is ideally suited to this candidate who has completed her professional veterinary degree, clinical pathology training and PhD in Comparative Pathology but has not completed postdoctoral research training. Currently, the candidate is a junior faculty member at a strong research institution with a clear mandate and desire to pursue an independent research program.