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: 10457368
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457368
• 关键词: Address; Adenovirus Infections; Adenovirus Protein; Adenoviruses; 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; 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; Western Blotting; 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.

项目总结 逃避抗病毒免疫反应的需要推动了病毒策略的进化，以操纵宿主细胞 染色质，控制基因表达并颠覆细胞防御。腺病毒是无处不在的病毒， 为理解基本的细胞过程提供了重要的模型系统，以及 用于治疗目的的载体。腺病毒及其衍生载体感染可激发强大的先天免疫 反应，既影响病程，也影响其作为基因传递和 接种疫苗。因此，了解破坏宿主反应的病毒蛋白对于治疗 感染和改进治疗媒介的应用。在这里，我们集中在腺病毒蛋白VII，主要的 一种核心蛋白质，以前被认为只起包装病毒基因组的作用。我们发现 在腺病毒感染期间，蛋白VII在病毒和宿主基因组上都具有意想不到的作用。长的- 这个项目的学期目标是破译这种类似组蛋白的病毒蛋白是如何克服先天宿主反应和 促进传染性病毒后代的产生。我们最近发现，蛋白VII与DNA结合， 核小体，具有类似于组蛋白的转录后修饰(PTM)，并在 感染过程中的染色质。我们证明了蛋白vii可以改变宿主蛋白的组成。 与感染细胞的细胞核中的病毒基因组有关，也将宿主因子隔离在细胞中 染色质。我们的中心假设是，腺病毒蛋白vii模仿组蛋白，作为潜伏的 同时操纵病毒和细胞染色质以颠覆固有宿主反应的策略。这部小说 假设是在我们实验室用新工具产生的大量初步数据的基础上提出的 我们已经研究了蛋白VII是如何必要和充分地对抗细胞免疫反应的。 这两个综合的特定目标旨在通过研究蛋白vii的功能来验证我们的假设。 病毒和细胞基因组。目标1将确定病毒基因组上蛋白VII在感染过程中的功能。 生物化学和分子实验将解决蛋白质vii如何利用宿主机制促进 感染性后代的产生。目标2将研究蛋白VII对细胞染色质和 基因组结构。基因组和细胞方法将决定蛋白VII如何与 细胞蛋白质和染色体组起到抵消抗病毒宿主反应的作用。我们有 组建了一个跨学科的协作团队来确定这种核心病毒组蛋白样蛋白的颠覆性 一个项目中的细胞先天性免疫反应对理解病毒如何引发 染色质的变化，以克服宿主的防御。