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: 9979734
• 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/9979734
• 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; combat; 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