Cellular Targets of the BKPyV miRNA

BKPyV miRNA 的细胞靶标

• 批准号: 9975095
• 负责人: MICHAEL J. IMPERIALE
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-09 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975095
• 关键词: BK Virus; Biology; Cell Communication; Cells; Chromosomes; Code; Complex; DNA; DNA Viruses; DNA biosynthesis; Disease; Environment; Genes; Genetic; Genetic Transcription; Genome; Human; Immune system; Immunoprecipitation; Individual; Infection; Integration Host Factors; Messenger RNA; MicroRNAs; Modeling; Natural Killer Cells; Nonstructural Protein; Nucleic Acids; Outcome; Polyomavirus; Polyomavirus Infections; Population; Proteins; Regulation; Role; S Phase; Small Interfering RNA; Small RNA; Testing; Therapeutic Intervention; Tissues; Translations; Transplant Recipients; Tumor Antigens; Untranslated RNA; Urinary tract; Validation; Variant; Viral; Viral Genes; Viral Genome; Viral Tumor Antigens; Virus; Virus Diseases; Virus Replication; cell growth; cellular targeting; chronic infection; effective therapy; genetic regulatory protein; insight; knock-down; lytic replication; macromolecule; new therapeutic target; novel therapeutic intervention; particle; recruit; synthetic construct; transcriptome sequencing; tumor; viral DNA

Viruses encode multifunctional non-structural proteins in order to accommodate as much coding potential as possible into their relatively small genomes. Many of these proteins often interact with multiple host cell factors to manipulate the host environment to make it more conducive to virus replication and to help the virus evade the immune system, for example. Various viruses also express non-coding RNA molecules such as microRNAs (miRNAs), but the roles of these miRNAs are much less well understood. It stands to reason that, as is the case for non- structural proteins, viruses would evolve to maximize the utility of the miRNAs. BK polyomavirus (BKPyV) is a small DNA virus that is ubiquitous in the human population. In healthy individuals, it persists in the urinary tract without causing obvious disease, but in transplant patients, uncontrolled virus replication has serious outcomes. BKPyV encodes two miRNAs from a single pre-miRNA precursor. These miRNAs downregulate expression of the viral tumor (T) antigens, multifunctional proteins that facilitate virus replication by stimulating S phase entry and recruiting the host DNA synthetic machinery to the viral chromosome. These miRNAs do not affect replication of disease-associated genetic BKPyV variants, but severely limit replication of the archetype, or wild type, virus that circulates through the population and establishes a persistent infection. In this proposal, we will test the hypothesis that like their protein counterparts, the miRNAs are multifunctional macromolecules that also target host factors to facilitate virus infection. The two aims are to identify host targets and begin to assess the role of those targets in BKPyV infection.

病毒编码多功能非结构蛋白，以适应尽可能多的编码 潜力尽可能地进入其相对较小的基因组。这些蛋白质中的许多经常相互作用 具有多种宿主细胞因素来操纵宿主环境，以使其更有利于 例如，病毒复制并帮助病毒逃避免疫系统。各种病毒 还表达非编码的RNA分子，例如microRNA（miRNA），但它们的作用 miRNA知之甚少。有理由认为，与非 - 结构蛋白，病毒将演变为最大化miRNA的效用。 BK多瘤病毒 （BKPYV）是一种在人群中无处不在的小型DNA病毒。在健康的个体中 它持续存在于尿路中而不会引起明显的疾病，但是在移植患者中， 不受控制的病毒复制具有严重的结果。 bkpyv编码一个来自单个的miRNA 前体前体。这些miRNA下调病毒肿瘤（T）抗原的表达， 多功能蛋白质通过刺激S相进入和募集来促进病毒复制的蛋白质 宿主DNA合成机械的病毒染色体。这些miRNA不影响 复制疾病相关的遗传BKPYV变体，但严重限制了复制的复制 原型或野生类型的病毒，通过人口流通并建立持久性 感染。在此提案中，我们将检验以下假设，即它们的蛋白质对应物， miRNA是多功能的大分子，也针对宿主因子以促进病毒 感染。这两个目标是识别宿主目标并开始评估这些目标的作用 在BKPYV感染中。