Viral Long Noncoding RNA Functions in Epstein-Barr Virus Infection

病毒长非编码 RNA 在 Epstein-Barr 病毒感染中的功能

基本信息

批准号：
8806522
负责人：
JEFFERY T SAMPLE
金额：
$ 37.17万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8806522
关键词：
Acquired Immunodeficiency Syndrome Adoption B-Lymphocytes CCCTC-binding factor Cells Cellular Immunity Chromatin Chromatin Loop Complex Control Locus DNA replication origin Data Development Disease Distal Epstein-Barr Virus Infections Epstein-Barr Virus latency Equilibrium Event Gene Duplication Gene Expression Genes Genetic Transcription Genome Herpesviridae Human Human Herpesvirus 4 Immune Individual Infection Infectious Mononucleosis Introns Knowledge Life Location Lymphoma Lymphoproliferative Disorders Lytic Phase Maintenance Malignant Neoplasms Mediating Medical Memory B-Lymphocyte Messenger RNA MicroRNAs Molecular Conformation Nucleotides Oncogenic Patients Pattern Play Process Property Protein Binding Proteins RNA RNA Splicing Recombinants Regulation Research Rest Risk Factors Role Small Nucleolar RNA Testing Transcript Untranslated RNA Viral Viral Genes Viral Genome Viral Proteins Virus Virus Latency Virus Replication cofactor defined contribution immunosuppressed latency-associated protein latent infection paralogous gene pathogen persistent EBV infection programs promoter protein expression public health relevance trafficking viral RNA

项目摘要

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is an extremely successful pathogen, being able to establish a lifelong latent infection within B lymphocytes of its human host, with overt disease in healthy individuals restricted to a self- limiting mononucleosis in ~40% of individuals when infection is delayed until the second decade of life. However, a breakdown in cellular immunity, particularly as a consequence of AIDS, remains a significant risk factor for development of EBV-associated lymphoma and lymphoproliferative disease, underscoring the highly evolved equilibrium that exists between EBV and its host. Establishment of this equilibrium, and EBV's oncogenic potential are dependent on a highly coordinated and controlled expression of the EBV latency- associated genes, which encode not only proteins but at least four classes of noncoding RNAs (ncRNAs). The long-term objective of the research proposed in this application is to understand the contributions made to EBV infection and pathogenic potential by two EBV RNAs belonging to the class of long ncRNAs (lncRNAs), i.e., RNAs longer than 200 nucleotides with little or no functional protein-encoding capability. These lncRNAs are encoded by the paralogous EBV genes BHLF1 and LF3, long known to be expressed at high level during the virus replication or lytic cycle, but recently identified as beig actively expressed during latent infection as well. Our preliminary results indicate that, upon deletion of the BHLF1 locus from the EBV genome, the virus is unable to sustain full expression of the EBV latency-associated proteins, converting to a more restricted program of latency-gene expression associated with long-term EBV persistence within its cellular reservoir, the memory B cell. Thus, we hypothesize that the BHLF1 lncRNA, and its paralog from LF3, play active but distinct roles in the regulation of EBV latent infection and persistence. We propose four specific aims: Under Aim 1, we will identify proteins that interact with the BHLF1 lncRNA, and the role that these specific RNA:protein associations play in EBV latent infection. In Aim 2 we will elucidate the expression patterns of the BHLF1 lncRNAs during the different EBV latency programs (defined by specific patterns of viral gene expression), and whether they traffic to specific subcellular domains with known functionality, possibly revealing function(s) of the EBV lncRNA. In Aim 3 we will elucidate whether the BHLF1 gene locus itself, in concert with its lncRNA, acts as a central determinant of EBV latency program by regulating viral genome configuration and other mechanisms. Finally, under Aim 4 we will begin to define the roles that the LF3 locus and lncRNA contribute to EBV latency, taking a similar tack as we have proposed for BHLF1.

描述（由申请人提供）：Epstein-Barr病毒（EBV）是一种非常成功的病原体，能够在其人类宿主的B淋巴细胞内建立终生的潜在感染，在健康个体中，当感染延迟到第二十年时，健康个体的明显疾病仅限于自我限制的单核病。然而，细胞免疫的细分，特别是由于艾滋病的结果，仍然是EBV相关淋巴瘤和淋巴增生性疾病发展的重要危险因素，强调了EBV与宿主之间存在的高度发展的平衡。建立这种平衡，EBV的致癌潜力取决于EBV潜伏期相关基因的高度协调和受控的表达，该基因不仅编码蛋白质，而且编码至少四类非编码RNA（NCRNA）。本应用中提出的研究的长期目标是了解属于长NCRNA类（LNCRNA）类别的EBV感染和致病潜力的贡献，即较少或没有功能性蛋白质剂量能力的RNA超过200个核苷酸。这些LNCRNA由寄生虫EBV基因BHLF1和LF3编码，该基因在病毒复制或裂解周期期间以高水平表达，但最近被确定为在潜在感染期间主动表达的贝格。我们的初步结果表明，在从EBV基因组中删除BHLF1基因座后，该病毒无法维持与EBV潜伏期相关蛋白的完全表达，转化为更受限制的延迟基因表达程序，与其长期EBV持久性相关的延迟 - 基因表达程序在其蜂窝储量内的长期EBV持久性。因此，我们假设BHLF1 lncRNA及其来自LF3的旁系同源物在EBV潜在感染和持久性的调节中起积极但独特的作用。我们提出了四个具体目标：在AIM 1下，我们将确定与BHLF1 lncRNA相互作用的蛋白质，以及这些特定RNA：蛋白质关联在EBV潜伏感染中起起的作用。在AIM 2中，我们将阐明在不同的EBV潜伏期程序（由病毒基因表达的特定模式定义），以及它们是否访问具有已知功能的特定亚细胞域，可能揭示EBV lncRNA的功能。在AIM 3中，我们将通过调节病毒基因组构型和其他机制来阐明BHLF1基因基因座本身是否与其LNCRNA结合起来是EBV潜伏期程序的中心决定因素。最后，在AIM 4下，我们将开始定义LF3基因座和LNCRNA促进EBV潜伏期的角色，并采用了我们对BHLF1的类似作用。