Granulocytic Ehrlichiosis: Cell-Pathogen Interactions

描述（由申请人提供）：人粒细胞埃利希体病（HGE）是一种新兴的、潜在致命的、由专性细胞内细菌引起的蜱传人畜共患病。虽然嗜吞噬细胞无原体，以前的HGE试剂，主要在粒细胞内生存和复制，但多发性细胞减少，特别是血小板减少，是感染的一致标志。嗜吞噬芽胞杆菌在体内与中性粒细胞和血小板的相互作用，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。该项目的目标是利用小鼠HGE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。研究目的首先是确定白细胞和血小板与嗜吞噬胞杆菌的相互作用和反应，其次是确定这些相互作用在确定病原体分布和传播中的作用（如果有的话）。根据初步数据，本研究的中心假设是，在感染早期，嗜吞噬胞杆菌粘附并激活粒细胞和血小板，导致细胞粘附和分布的改变，直接影响细胞-病原体的运输，促进病原体的复制和传播。提出的工作是集中在一个新兴的，人畜共患疾病与潜在的严重血液学改变。这项工作的重大积极影响将包括加强对体内细菌发病机制的理解，以及阐明从动物宿主到蜱虫媒介传播周期中断的可能目标。拟议的指导临床科学家发展（KO8）奖的目的是为候选人提供过渡到独立学术临床科学家职位所需的指导和资源。该奖项非常适合已完成兽医专业学位、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，候选人是一个强大的研究机构的初级教员，有明确的任务和追求独立的研究项目的愿望。

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.