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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）是由嗜吞噬细胞无形体引起的一种新出现的蜱传疾病，嗜吞噬细胞无形体是中性粒细胞的专性细胞内细菌。A.吞噬细胞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炎症招募新的中性粒细胞，组织损伤，炎症调节无效，抗菌反应差。我们研究了嗜吞噬细胞芽胞杆菌感染后中性粒细胞功能的改变，并重点研究了核效应蛋白AnkA如何被递送到宿主细胞中，与受感染调控的基因启动子结合，诱导表观遗传染色质重塑和转录重编程。嗜吞噬单胞菌感染的粒细胞转录组显示了许多促进感染的差异转录基因[3-6]。鉴于嗜吞噬芽胞杆菌基因组资源贫乏，很难解释单个易位效应蛋白对宿主转录变化和功能重编程的程度。这意味着细菌对包括染色质和组蛋白重塑在内的全球基因转录产生影响，可能是通过靶向转录调控的保守机制，如细胞分化和肿瘤形成。AnkA具有作为基质附着区域结合蛋白的功能，可以调节染色体区域对转录修饰剂的访问，这是细菌-宿主相互作用的新范式。我们假设AnkA与一些转录调控基因的启动子结合，修饰或招募表观遗传染色质标记或转录因子的修饰子。此外，我们假设嗜吞噬细胞芽胞杆菌通过AnkA对核基质、染色质和转录装置募集的作用改变了表观基因组，从而对全球中性粒细胞转录组进行了重编程。我们提出以下目标：确定CYBB启动子中的AnkA结合位点，确定参与CYBB启动子结合和转录活性的AnkA结构域或基序。2. 确定AnkA是否通过直接作用于CYBB启动子或通过募集染色质重塑或转录因子影响宿主基因转录。3. 确定AnkA是否作为一种基质附着区域结合蛋白，在全局转录调控中将DNA连接到核基质上，调节DNA环域，并允许其他染色质修饰因子对接。细菌对细胞转录的影响越来越被认识到。验证这些假设将为原核生物控制真核生物的潜在强大机制提供证据。长期目标是发展对细菌与宿主细胞密切联系如何规避宿主功能的机制理解。这些信息可以让HGA得到合理的预防和治疗，但也可以跨越生物学和医学，因为这些分子可以被设计成表观遗传工具或治疗方法。