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，以容纳尽可能多的编码 尽可能将其潜力融入到相对较小的基因组中。许多这些蛋白质经常相互作用 利用多种宿主细胞因子来操纵宿主环境，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 也表达非编码 RNA 分子，例如 microRNA (miRNA)，但这些分子的作用 miRNA 的了解要少得多。按理说，与非的情况一样 结构蛋白、病毒将进化以最大化 miRNA 的效用。 BK多瘤病毒 (BKPyV) 是一种小型 DNA 病毒，在人群中普遍存在。在健康个体中， 它持续存在于泌尿道中，不会引起明显的疾病，但在移植患者中， 不受控制的病毒复制会产生严重后果。 BKPyV 从单个 miRNA 中编码两个 miRNA pre-miRNA 前体。这些 miRNA 下调病毒肿瘤 (T) 抗原的表达， 多功能蛋白，通过刺激 S 期进入和招募来促进病毒复制 宿主 DNA 合成机器到病毒染色体。这些 miRNA 不影响 疾病相关遗传 BKPyV 变体的复制，但严重限制了 BKPyV 基因的复制 原型或野生型病毒，在人群中传播并建立持久的 感染。在这个提案中，我们将测试这样一个假设：就像它们的蛋白质对应物一样， miRNA 是多功能大分子，也针对宿主因子以促进病毒传播 感染。这两个目标是确定宿主目标并开始评估这些目标的作用 在 BKPyV 感染中。