EBV infection control by RNA surveillance

通过 RNA 监测控制 EBV 感染

• 批准号: 10283975
• 负责人: Michaela Ulrike Gack
• 金额: $ 20.13万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283975
• 关键词: Acute; Affinity Chromatography; Antiviral Agents; Antiviral Response; Antiviral Therapy; B-Lymphocytes; Biochemical; Biological; Biological Assay; Burkitt Lymphoma; Cell Culture System; Cell physiology; Cells; DNA Tumor Viruses; DNA Viruses; Data; Defense Mechanisms; Development; Disease; EBV reactivation from latency; EBV-associated disease; Engraftment; Epithelial; Epithelial Cells; Epithelium; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Foundations; Genetic Transcription; Goals; Hodgkin Disease; Host Defense; Host Defense Mechanism; Human; Human Herpesvirus 4; Immune; Immune response; Immunologic Receptors; In Vitro; Individual; Infection Control; Interferons; Intrinsic factor; Knowledge; Laboratories; Latent virus infection phase; Lead; Life Cycle Stages; Link; Lymphoproliferative Disorders; Lytic; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Molecular Genetics; Mus; Nasopharynx Carcinoma; Nonsense-Mediated Decay; Pathogenesis; Pathway interactions; Physiological; Play; Proteins; RNA; RNA Decay; RNA Degradation; RNA Viruses; Regulation; Research; Role; Series; Stomach Carcinoma; Trans-Activators; Transcript; Tumor Virus Infections; Viral; Virus; Virus Diseases; Virus Replication; Work; cell growth; cell growth regulation; cell immortalization; cell type; cytokine; defined contribution; design; gammaherpesvirus; in vivo; innovation; mRNA Decay; mortality; mouse model; next generation; novel; novel therapeutics; post-transplant; receptor; sensor; transcriptome sequencing; tumor; tumorigenesis; viral RNA

PROJECT SUMMARY Both establishment of latency by Epstein–Barr virus (EBV) and the virus’ ability to reactivate are prerequisites for EBV-associated diseases including B cell- and epithelial cell- derived malignancies. Yet, large gaps in knowledge about the host cell-intrinsic factors that regulate the establishment and maintenance of EBV latency and the life cycle of EBV overall exist. Among the host innate immune/intrinsic mechanisms that are critical for controlling virus replication are several RNA surveillance pathways, most prominently the ones initiated by intracellular RNA sensors, such as RIG-I-like receptors, that induce interferon-mediated antiviral responses. Another important eukaryotic RNA surveillance pathway is the nonsense-mediated mRNA decay (NMD) pathway which recognizes and rapidly degrades certain RNAs. Whereas the role of the NMD machinery in the regulation of cellular processes has been well defined, significantly less is known about the relevance of NMD-mediated RNA decay in controlling virus replication. Intriguingly, a series of recent studies demonstrated that the NMD pathway is critical for restricting the replication of several RNA viruses; however, whether NMD-mediated RNA decay plays a role in controlling the life cycle of DNA viruses, and in particular gamma- herpesviruses such as EBV, is currently unknown. The long-term goal of this study is to understand the physiological relevance of the NMD RNA surveillance machinery in controlling the EBV life cycle (Aim 1). We will utilize molecular and biochemical assays combined with next-generation RNA sequencing to determine the precise RNAs targeted by the NMD machinery in EBV-infected cells, and further elucidate the role of degradation of these RNAs in controlling EBV latent infection and reactivation in various relevant cell types (Aim 2). Finally, we will determine the role of NMD-mediated RNA surveillance in EBV-induced oncogenesis (Aim 3). The research proposed in this application is innovative because it investigates the role of a novel intrinsic host mechanism in EBV infection control and EBV-induced tumorigenesis. Furthermore, the proposed studies are important as they will significantly expand our knowledge about host regulation of EBV infection and likely guide the design of novel therapeutic strategies.

项目摘要 EB病毒（EBV）潜伏期的建立和病毒的能力， 活化是EBV相关疾病的先决条件，包括B细胞和上皮细胞， 衍生的恶性肿瘤。然而，关于宿主细胞内在因素的知识存在巨大差距， 从整体上调节EBV潜伏期的建立和维持以及EBV的生命周期 存在. 在控制病毒的宿主先天免疫/内在机制中， 复制是几种RNA监视途径，最突出的是由 诱导干扰素介导的抗病毒的细胞内RNA传感器，如RIG-I样受体 应答另一个重要的真核RNA监视途径是无义介导的 mRNA衰变（NMD）途径，其识别并快速降解某些RNA。而 NMD机制在调节细胞过程中的作用已经被很好地定义， 关于NMD介导的RNA衰变在控制病毒中的相关性， 复制的有趣的是，最近的一系列研究表明，NMD途径至关重要 限制几种RNA病毒的复制;然而，NMD介导的RNA是否 衰变在控制DNA病毒的生命周期中发挥着作用，特别是γ- 疱疹病毒如EBV目前是未知的。 这项研究的长期目标是了解NMD的生理相关性 RNA监视机制在控制EBV生命周期中的作用（Aim 1）。我们将利用分子 和生化分析结合下一代RNA测序，以确定 在EBV感染的细胞中，NMD机制靶向的精确RNA，并进一步阐明了NMD机制的作用。 这些RNA的降解在控制EB病毒潜伏感染和在各种疾病中的再活化中的作用， 相关细胞类型（目标2）。最后，我们将确定NMD介导的RNA的作用， 监测EBV诱导的肿瘤发生（目的3）。 本申请中提出的研究是创新的，因为它调查了 EBV感染控制和EBV诱导肿瘤发生的一种新的内在宿主机制。 此外，拟议的研究很重要，因为它们将大大扩展我们的知识 关于宿主对EBV感染的调节，并可能指导新的治疗方法的设计。 战略布局