Adenovirus manipulation of cellular chromatin to overcome host responses

腺病毒操纵细胞染色质以克服宿主反应

• 批准号: 10238103
• 负责人: Matthew D. Weitzman
• 金额: $ 54.24万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238103
• 关键词: Address; Adenovirus Infections; Adenovirus Protein; Adenoviruses; Antiviral Agents; Antiviral Response; Appearance; Architecture; Binding; Biochemical; Biological Models; Cell Nucleus; Cell physiology; Cells; ChIP-seq; Chromatin; Chromatin Structure; Core Protein; DNA; DNA Binding; DNA Damage; DNA Viruses; Data; Disease; Effectiveness; Enterobacteria phage P1 Cre recombinase; Evolution; Excision; Gene Delivery; Gene Expression; Genetic Transcription; Genome; Genomics; Goals; HMGB1 gene; Health; Histones; Host Defense; Human; Immune response; Immunoblotting; Infection; Inflammatory; Innate Immune Response; Integration Host Factors; Interferon Activation; Interferons; Knowledge; Lead; Major Core Protein; Malignant Neoplasms; Modification; Molecular; Mutation; Nature; Nucleic Acids; Nucleosomes; Oncolytic; Outcome; Physical condensation; Plaque Assay; Play; Production; Proteins; Proteomics; Public Health; Quantitative Reverse Transcriptase PCR; Resources; Role; Signal Transduction; Stimulus; System; Testing; Therapeutic; Vaccination; Viral; Viral Core Proteins; Viral Genes; Viral Genome; Viral Packaging; Viral Proteins; Virion; Virus; Virus Diseases; design; experimental study; genome-wide; human DNA; improved; novel; particle; pathogen; protein expression; protein function; recruit; response; sensor; tool; vector; viral DNA

PROJECT SUMMARY The need to evade antiviral immune responses has driven evolution of viral strategies to manipulate host cell chromatin, to control gene expression and subvert cellular defenses. Adenoviruses are ubiquitous viruses that have provided both important model systems for understanding fundamental cellular processes, as well as vectors for therapeutic purposes. Infections by Adenovirus and derived vectors elicit strong innate immune responses, which impact both the course of disease and their effectiveness as vectors for gene delivery and vaccination. Therefore understanding viral proteins that subvert host responses is important for treating infections and improving therapeutic vector applications. Here we focus on Adenovirus protein VII, the major core protein that was previously thought to function exclusively for packaging viral genomes. We discovered that protein VII has unexpected roles on both viral and host genomes during Adenovirus infection. The long- term goal of this project is to decipher how this histone-like viral protein overcomes innate host responses and promotes production of infectious viral progeny. We recently showed that protein VII binds DNA and nucleosomes, possesses post-transcriptional modifications (PTMs) analogous to histones, and accumulates in chromatin during infection. We demonstrated that protein VII can alter the composition of host proteins associated with viral genomes in the nuclei of infected cells, and also sequesters host factors in cellular chromatin. Our central hypothesis is that Adenovirus protein VII mimics histones as part of an insidious strategy that manipulates both viral and cellular chromatin to subvert innate host responses. This novel hypothesis has been formulated on the basis of extensive preliminary data produced in our lab with new tools we have generated to study how protein VII is necessary and sufficient to counter cellular immune responses. The two integrated Specific Aims are designed to test our hypothesis by studying functions of protein VII on viral and cellular genomes. Aim 1 will define functions of protein VII on the viral genome during infection. Biochemical and molecular experiments will address how protein VII exploits host machinery to promote production of infectious progeny. Aim 2 will examine the impacts of protein VII on cellular chromatin and genome architecture. Genomic and cellular approaches will determine how association of protein VII with cellular proteins and the chromatinized genome serves to counteract antiviral host responses. We have assembled an interdisciplinary collaborative team to determine this core viral histone-like protein subverts cellular innate immune responses in a project that has broader implications for understanding how viruses elicit changes in chromatin to overcome host defenses.

项目概要 逃避抗病毒免疫反应的需要推动了病毒操纵宿主细胞策略的进化 染色质，控制基因表达并破坏细胞防御。腺病毒是普遍存在的病毒 提供了理解基本细胞过程的重要模型系统，以及 用于治疗目的的载体。腺病毒和衍生载体的感染引发强大的先天免疫 反应，影响疾病的进程及其作为基因传递载体的有效性 疫苗接种。因此，了解破坏宿主反应的病毒蛋白对于治疗很重要 感染和改善治疗载体应用。在这里，我们重点关注腺病毒蛋白 VII，它是主要的 以前被认为专门用于包装病毒基因组的核心蛋白。我们发现 在腺病毒感染期间，蛋白质 VII 对病毒和宿主基因组都具有意想不到的作用。长- 该项目的长期目标是破译这种组蛋白样病毒蛋白如何克服先天宿主反应并 促进传染性病毒后代的产生。我们最近证明蛋白 VII 结合 DNA 并 核小体，具有类似于组蛋白的转录后修饰（PTM），并在 感染期间的染色质。我们证明蛋白 VII 可以改变宿主蛋白的组成 与受感染细胞核中的病毒基因组相关，并且还隔离细胞中的宿主因子 染色质。我们的中心假设是，腺病毒蛋白 VII 模仿组蛋白，作为一种阴险的机制的一部分。 操纵病毒和细胞染色质以颠覆宿主先天反应的策略。这部小说 假设是根据我们实验室使用新工具产生的大量初步数据制定的 我们的目的是研究蛋白质 VII 对于对抗细胞免疫反应是必要且充分的。 这两个综合的具体目标旨在通过研究蛋白质 VII 的功能来检验我们的假设。 病毒和细胞基因组。目标 1 将定义感染期间病毒基因组上蛋白 VII 的功能。 生化和分子实验将解决蛋白质 VII 如何利用宿主机制来促进 产生传染性后代。目标 2 将检查蛋白质 VII 对细胞染色质和 基因组结构。基因组和细胞方法将确定蛋白质 VII 如何与 细胞蛋白和染色质基因组可以抵消宿主的抗病毒反应。我们有 组建了一个跨学科合作团队来确定这种核心病毒组蛋白样蛋白颠覆 该项目中的细胞先天免疫反应对于理解病毒如何引发具有更广泛的影响 染色质的变化以克服宿主的防御。