Granulocytic Ehrlichiosis: Cell-Pathogen Interactions

描述（由申请方提供）：人粒细胞埃立克体病（HGE）是一种由专性细胞内细菌引起的新发、潜在致死性、蜱媒人畜共患疾病。尽管嗜吞噬细胞无形体（以前的HGE因子）主要在粒细胞内生活和复制，但多发性血细胞减少症，特别是血小板减少症，是感染的一致标志。A.嗜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、血细胞减少、病原体分布和传播的影响方式仍不清楚。本项目的目的是了解病原体与宿主细胞的相互作用，根据血液学异常和体内感染动力学，利用小鼠模型的HGE和体外细胞技术。研究目的首先是确定白细胞和血小板与A.第二，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，这项研究的中心假设是，在感染早期，A。嗜吞噬细胞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-病原体运输并促进病原体复制和传播。拟议的工作重点是一种新出现的人畜共患疾病，具有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，以及阐明中断从动物宿主到蜱媒的传播周期的可能目标。拟议的指导临床科学家发展（KO 8）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。该奖项非常适合这位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，候选人是一个强大的研究机构的初级教员，有明确的任务和愿望，追求独立的研究计划。

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.