Granulocytic Ehrlichiosis: Cell-Pathogen Interactions

粒细胞埃利希体病：细胞-病原体相互作用

• 批准号: 6730558
• 负责人: DORI L. BORJESSON
• 金额: $ 12.81万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6730558
• 关键词: Rickettsiales; SDS polyacrylamide gel electrophoresis; bacteria infection mechanism; cell adhesion; clinical research; ehrlichiosis; electron microscopy; flow cytometry; genetically modified animals; granulocyte; host organism interaction; human tissue; immunofluorescence technique; laboratory mouse; leukocytes; neutrophil; platelets; polymerase chain reaction; thrombocytopenia; ticks; western blottings; zoonosis

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.

描述（由申请人提供）：人类粒细胞eHrllichiois（HGE）是一种新兴的，潜在的致命的，tick虫的人畜共患病，是由强制性细胞内细菌引起的。尽管以前是HGE剂的Anaplasma phocytophila主要在粒细胞中生存并复制，但多个细胞质（尤其是血小板减少症）是感染的一致标志。吞噬曲霉与体内中性粒细胞和血小板的相互作用以及这些相互作用有助于感染效率，细胞质，病原体分布和传播的方式的相互作用尚不清楚。该项目的目的是通过使用HGE和体外细胞技术的鼠模型来理解血液学异常和体内感染动力学的病原体相互作用。研究目标首先是为了确定白细胞和血小板相互作用，并响应于吞噬细胞嗜酸杆菌，其次，确定这些相互作用在确定病原体分布和传播方面起着作用。基于初步数据的拟议研究的中心假设是，在早期感染期间，吞噬细胞the虫粘附并激活粒细胞和血小板，导致细胞粘附和分布的改变，导致直接影响细胞path的细胞粘附和分布改变，并促进病原体复制和传播。拟议的工作集中于一种新兴的人畜共患病，并具有严重的血液学改变。这项工作的重大积极影响将包括对体内细菌发病机理的理解以及阐明从动物宿主到tick载体的传播周期中断可能的靶标。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医生 - 科学家职位所需的指导和资源。该奖项非常适合该候选人，该候选人在比较病理学中完成了她的专业兽医学位，临床病理培训和博士学位，但尚未完成博士后研究培训。目前，该候选人是一家强大的研究机构的初级教职员工，具有明确的任务和渴望追求独立研究计划的愿望。