Anaplasma regulation of host granulocyte function

无形体对宿主粒细胞功能的调节

基本信息

批准号：
8769555
负责人：
JOHN STEPHEN Dumler
金额：
$ 16.57万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8769555
关键词：
17q23.1 6p21.3 ABI1 gene Acetylation Adhesions Affect Affinity Anaplasma Anaplasma phagocytophilum Ankyrins Antibodies Apoptosis Architecture Bacteria Binding Binding Proteins Binding Sites Biology Blood Circulation Bovine Anaplasmosis Cell Nucleus Cell Survival Cell physiology Cells ChIP-on-chip Chromatin Chromatin Loop Chromatin Remodeling Factor Chromosome Territory Chromosomes Co-Immunoprecipitations Complex Cytosol DNA DNA Binding DNA-Binding Proteins Data Deacetylase Disease Docking EMSA Elements Endothelium Engineering Enzymes Epigenetic Process Eukaryota Fostering Gene Activation Gene Expression Profile Gene Silencing Gene-Modified Genes Genetic Transcription Genome Genomics Goals Health Histone Deacetylation Histones Host Defense Human Individual Infection Inflammation Inflammatory Injury Integrins Investigation Kinetics Learning Length Life Lysine MHC Class I Genes Mass Spectrum Analysis Matrix Attachment Regions Medicine Messenger RNA Metalloproteases Methylation Methyltransferase Mutate Mutation Neoplasms Normal Cell Nuclear Nuclear Matrix Nuclear Protein Nuclear Proteins Organism Oxidases Pathogenesis Peroxidases Phagocytes Phagocytosis Pharmaceutical Preparations Prevention approach Prevention therapy Process Production Property Protein Binding Proteins Recruitment Activity Regulation Reporter Resources Respiratory Burst Rickettsiales Role Signal Pathway Signal Transduction Site Small Interfering RNA Structure Testing Therapeutic Agents Tick-Borne Diseases Ticks Tissues Transcriptional Regulation antimicrobial base cell motility chemokine chromatin remodeling eosinophil peroxidase epigenome genome-wide granulocyte killings microbicide mutant neutrophil novel pathogen promoter response tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Human granulocytic anaplasmosis (HGA) is an emerging tick-borne disease caused by Anaplasma phagocytophilum, an obligate intracellular bacterium of neutrophils. A. phagocytophilum infection impairs neutrophil function by transcriptional reprogramming, where the reprogrammed neutrophil promotes inflammatory recruitment of new neutrophils, tissue injury, ineffective regulation of inflammation, and poor antimicrobial responses. We studied altered neutrophil function with A. phagocytophilum infection and focused on how the nuclear effector protein AnkA, when delivered into the host cell where it binds to promoters of genes regulated with infection, induces epigenetic chromatin remodeling and transcriptional reprogramming. The granulocyte transcriptome with A. phagocytophilum infection shows a number of differentially transcribed genes that promote infection [3-6]. Given the meager genomic resources of A. phagocytophilum, it is difficult to explain the extent of host transcriptional change and functional reprogramming by individual translocated effector proteins. This implies that the bacterium exerts influence over global gene transcription, including chromatin and histone remodeling, perhaps by targeting conserved mechanisms of transcriptional regulation such as in cellular differentiation and neoplasia. AnkA has properties that suggest function as a matrix attachment region-binding protein that could regulate access of chromosomal territories to transcriptional modifiers, a new paradigm in bacteria-host interactions. We hypothesize that AnkA binds to promoters of some transcriptionally regulated genes and modifies or recruits modifiers of epigenetic chromatin marks or transcription factors. In addition, we hypothesize that A. phagocytophilum reprograms the global neutrophil transcriptome by altering the epigenome through AnkA"s action on nuclear matrix, chromatin, and transcriptional apparatus recruitment. We propose the following aims: 1. To identify AnkA binding sites in the CYBB promoter and to define AnkA domains or motifs involved in CYBB promoter binding and transcriptional activity. 2. To determine whether AnkA affects host gene transcription through direct action at the CYBB promoter or through recruitment of chromatin remodeling or transcription factors. 3. To determine whether AnkA functions as a matrix attachment region-binding protein that tethers DNA to nuclear matrix, regulates DNA loopscape, and permits docking of other chromatin modifiers in global transcriptional regulation. The effects that bacteria have over cellular transcription are increasingly recognized. Testing these hypotheses will provide evidence of a potentially powerful mechanism for prokaryotic control over eukaryotes. The long- term goals are to develop a mechanistic understanding of how bacteria with intimate host cell associations circumvent host functions. This information could allow rational preventions and therapies for HGA, but could also span biology and medicine, since such molecules could be engineered as epigenetic tools or therapies.

描述（由申请人提供）：人粒细胞无形体病（HGA）是一种新出现的蜱传疾病，由嗜吞噬细胞无形体（一种嗜中性粒细胞的专性细胞内细菌）引起。嗜吞噬细胞球菌感染通过转录重编程损害中性粒细胞功能，其中重编程的中性粒细胞促进新中性粒细胞的炎症募集、组织损伤、炎症调节无效和抗菌反应不良。我们研究了嗜吞噬细胞球菌感染对中性粒细胞功能的改变，并重点研究了核效应蛋白 AnkA 在被递送到宿主细胞中时如何与受感染调节的基因启动子结合，从而诱导表观遗传染色质重塑和转录重编程。嗜吞噬细胞球菌感染的粒细胞转录组显示许多促进感染的差异转录基因[3-6]。鉴于嗜吞噬细胞曲霉的基因组资源贫乏，很难解释宿主转录变化的程度和单个易位效应蛋白的功能重编程。这意味着细菌可能通过针对细胞分化和肿瘤形成等转录调控的保守机制来对整体基因转录产生影响，包括染色质和组蛋白重塑。 AnkA 具有作为基质附着区域结合蛋白的特性，可以调节染色体区域与转录修饰剂的接触，这是细菌与宿主相互作用的新范例。我们假设 AnkA 与一些转录调控基因的启动子结合，并修饰或招募表观遗传染色质标记或转录因子的修饰剂。此外，我们假设 A. phagocytophilum 通过 AnkA 对核基质、染色质和转录装置招募的作用改变表观基因组，从而重新编程全局中性粒细胞转录组。我们提出以下目标： 1. 鉴定 CYBB 中的 AnkA 结合位点2. 确定 AnkA 是否通过直接作用影响宿主基因转录。 CYBB 启动子或通过招募染色质重塑或转录因子 3. 确定 AnkA 是否作为基质附着区结合蛋白发挥作用，将 DNA 束缚在核基质上，调节 DNA 环景，并允许在全局转录调控中对接其他染色质修饰剂。人们越来越多地认识到细菌对细胞转录的影响，测试这些假设将为原核生物控制真核生物提供潜在的强大机制的证据。长期目标是对与宿主细胞密切相关的细菌如何规避宿主功能形成机制理解。这些信息可以为 HGA 提供合理的预防和治疗，但也可以跨越生物学和医学，因为此类分子可以被设计为表观遗传工具或疗法。