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Research Project 1: Role of Epigenetic and Transcriptional Mechanisms in the Pathogenesis of Ebola Virus Disease

研究项目1：表观遗传和转录机制在埃博拉病毒疾病发病机制中的作用

基本信息

批准号：
10188759
负责人：
Alexander Bukreyev
金额：
$ 42.55万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10188759
关键词：
2019-nCoV ATAC-seq Acute Address Animals Antiinflammatory Effect Apoptosis Area B-Lymphocytes Bioinformatics Cell physiology Cells Cessation of life ChIP-seq Chemicals Chromatin Collaborations Cytoplasm Data Data Analyses Dendritic Cells Deposition Development Disease Ebola Ebola Hemorrhagic Fever Ebola virus Ebola virus envelope glycoprotein Endothelial Cells Enzymes Epigenetic Process Equilibrium Gene Activation Gene Expression Genes Genetic Transcription Hepatocyte Human Immune Immune Tolerance Immune response Immunity Immunology In Vitro Infection Inflammation Inflammation Mediators Inflammatory Interferon-alpha Interferons Investigation Joints Journals Knowledge Lymphopenia Marburgvirus Mediating Mediator of activation protein Methods Modeling Molecular Mus Myelogenous Nature Outcomes Research Paper Pathogenesis Pathogenicity Pathologic Pharmacology Physiological Process Production Protein Isoforms Publishing Research Research Personnel Research Project Grants Role Science Signal Transduction Site T cell response T-Cell Activation T-Lymphocyte TLR4 gene Testing Topoisomerase Transcriptional Regulation Translational Regulation Treatment outcome Viral Pathogenesis Virus Virus Diseases Work base cell type cytokine cytokine release syndrome epigenetic regulation epigenome gene repression histone methylation in vivo inhibitor/antagonist innovation kidney cell mRNA Expression medical schools monocyte nonhuman primate pathogen programs proteogenomics response single cell analysis single cell sequencing transcription factor transcriptome transcriptome sequencing transcriptomics virology

项目摘要

RESEARCH PROJECT 1 (RP1): PROJECT SUMMARY/ABSTRACT Pathogenesis of the disease caused by Ebola virus (EBOV) is characterized by a multifaceted and contradictory interplay between the virus and the host. The effect of EBOV infection is characterized by deficient T-cell responses and lymphopenia, which at least in part results from stimulation by virus-infected dendritic cells whose maturation is suppressed by interferon-inhibiting domains of the virus. In addition, EBOV infections are characterized by hyperinflammation, contributed by interaction of the EBOV envelope glycoprotein (GP) with TLR4 on T cells and possibly by other mechanisms, resulting in massive secretion of cytokines. This dysregulated immune response results from disruption of transcriptional networks, many caused by alterations in the epigenome, as evidenced by (1) chemical inhibition of type 1 topoisomerase resulting in reduced expression of proinflammatory mediators induced by EBOV in infected cells, (2) inhibition of TLR4 signaling, which is regulated at epigenetic level, promoting survival of EBOV-infected mice, and (3) treatment of EBOV- infected mice with a global histone methylation inhibitor that upregulates production of IFNα and protects animals from death. The central hypothesis of Research Project 1 (RP1) is that cell-specific and gene-specific regulation of transcription in response to EBOV infection leads to contrasting responses that paradoxically cause a pathogenic immune response and “immune paralysis”. To address this hypothesis, the epigenetic and transcriptional landscape during EBOV infections in vitro and in vivo will be characterized. A comprehensive analysis of the transcriptome alterations and epigenetic changes caused by EBOV infection will be performed in both human primary cells and specific cell types isolated from infected nonhuman primates. Investigations involving the expression of mRNAs that encode transcription factors will be done to determine the deposition of epigenetic marks and their role in gene activation and repression, as well as investigating the effects of chromatin accessibility on expression and secretion of inflammatory mediators using cells from human donors. This project will target key transcriptional nodes identified by modeling EBOV infection. The data generated in vitro and in vivo, together with data from in RP2 and RP3, will be integrated by the Bioinformatics and Modelling Core (Core D) in a model. The transcriptional networks identified in the model will predict critical nodes that represent vulnerabilities that will be targeted to modulate cell response and reduce EBOV pathogenesis. For example, chromatin-resident enzymes and transcription factors that induce expression of genes causing inflammation and other pathological changes will be targeted. The study will result in the characterization of epigenetic and transcriptional responses to EBOV; to date no epigenetic response to any BSL-4 level virus has been characterized. The study will also result in the development of approaches to treat EBOV disease by targeting host transcriptional and epigenetic functions.

研究项目1(RP1)：项目摘要/摘要埃博拉病毒(Ebola Virus，EBOV)的发病机制具有多方面和矛盾性的特点病毒和宿主之间的相互作用。EBOV感染的影响以T细胞缺陷为特征反应和淋巴细胞减少，这至少部分是由病毒感染的树突状细胞刺激引起的，其成熟受到病毒干扰素抑制结构域的抑制。此外，EBOV感染是以过度炎症为特征，由EBOV包膜糖蛋白(GP)与 TLR4对T细胞的作用，可能通过其他机制，导致细胞因子的大量分泌。这免疫反应失调是由转录网络的破坏引起的，许多是由改变引起的在表观基因组中，如(1)化学抑制1型拓扑异构酶导致减少 EBOV诱导感染细胞中促炎症介质的表达，(2)抑制TLR4信号转导，它在表观遗传水平上受到调控，促进感染EBOV的小鼠存活，以及(3)治疗EBOV- 感染组蛋白甲基化抑制剂的小鼠上调干扰素α的产生并保护动物从死亡中脱身。研究项目1(RP1)的中心假设是细胞特异性和基因特异性调节对EBOV感染的转录反应导致反差反应，这矛盾地导致致病免疫反应和“免疫瘫痪”。为了解决这一假说，表观遗传和转录在体外和体内感染EBOV期间的景观将被描述。一项全面的分析由EBOV感染引起的转录组改变和表观遗传学改变将在两人中进行从受感染的非人灵长类动物中分离出的原代细胞和特定类型的细胞。调查涉及将进行编码转录因子的mRNAs的表达，以确定表观遗传的沉积标记及其在基因激活和抑制中的作用，以及研究染色质的影响使用人类供体细胞表达和分泌炎症介质的可及性。该项目将以通过模拟EBOV感染而确定的关键转录节点为目标。中生成的数据体外和体内，连同来自RP2和RP3的数据，将由生物信息学和模型中的建模核心(核心D)。模型中确定的转录网络将预测关键的代表漏洞的节点，将针对这些漏洞调整细胞响应并减少EBOV 发病机制。例如，染色质驻留酶和转录因子诱导表达引起炎症和其他病理变化的基因将成为目标。这项研究将导致对EBOV的表观遗传和转录反应的表征；到目前为止没有对任何BSL-4级别病毒的表观遗传反应已经被表征。这项研究还将导致开发针对宿主转录和表观遗传功能的治疗EBOV疾病的方法。