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EBV infection control by RNA surveillance

通过 RNA 监测控制 EBV 感染

基本信息

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
项目类别：
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

项目摘要

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.

项目总结