Targeting Apoptosis and Immune Control of Epstein-Barr Virus Infected Tonsillar B Cells

针对 Epstein-Barr 病毒感染的扁桃体 B 细胞的凋亡和免疫控制

• 批准号: 9237256
• 负责人: Micah A. Luftig
• 金额: $ 43.79万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-04 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9237256
• 关键词: Accounting; Adult; Antigen-Presenting Cells; Apoptosis; B Cell Proliferation; B-Cell Lymphomas; B-Lymphocytes; Blood Cells; CD8-Positive T-Lymphocytes; Cancer Etiology; Cell Survival; Cells; Complex; Data; Disease; Epithelial Cells; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Epstein-Barr Virus latency; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Genetic Transcription; Goals; HIV; HIV Infections; HIV-1; Hairy Leukoplakia; Haplotypes; Human; Human Herpesvirus 4; Immune; Immune Evasion; Immunosuppression; In Vitro; Individual; Infection; Lead; Life Cycle Stages; Lymphoid Tissue; Lymphoma; Lytic; MHC Class I Genes; Maintenance; Mediating; Membrane Proteins; Messenger RNA; Mitochondria; Modeling; Mouth Diseases; Oral; Oral Ulcer; Oral cavity; Pathogenesis; Periodontitis; Phase; Primary Infection; Process; Proteins; Research; Resistance; Saliva; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Tonsil; Transplantation; Up-Regulation; Viral; Viral Genes; Virus; Virus Diseases; Virus Latency; adaptive immune response; base; c-myc Genes; cohort; gammaherpesvirus; immunogenic; in vivo; infected B cell; killings; latent gene expression; lymphoblastoid cell line; pathogen; peripheral blood; prevent; programs; protein expression; public health relevance; therapeutic target; transforming virus

 DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is a gamma-herpesvirus that infects nearly 95% of adults worldwide. A potent adaptive immune response against the virus prevents disease in the majority of those infected. However, immune suppression, such as during HIV-1 infection, can promote latent EBV-driven B-cell lymphomas. It is our ultimate goal to define the mechanisms by which EBV establishes latency and how these processes go awry leading to disease. In this proposal, we aim to characterize a newly described early latent phase of EBV infection in primary tonsillar B cells and the mechanisms of EBV-mediated survival and immune evasion important for establishing and maintaining the latency reservoir. It is our central hypothesis that EBV promotes B-cell proliferation and survival through its EBV nuclear antigen (EBNA) proteins during the first two weeks of infection; while later during infection the EBNAs and latent membrane protein 1 (LMP1) are required for survival in the immortalized state. We propose that the importance of this biphasic EBV latent gene expression program is to prevent early recognition of EBV-infected B cells by cytotoxic T cells promoting efficient seeding of the long-term latently infected cell reservoir. We have formulated our central hypothesis based on preliminary data characterizing the temporal viral and host gene expression programs and survival mechanisms following EBV infection of peripheral blood B cells where we found that early after tonsillar B-cell infection, the viral EBNA proteins are expressed at high levels in the absence of appreciable levels of the viral LMPs. Importantly, this latency type (IIb) has been observed in EBV-associated post-transplant and HIV lymphomas. Therefore, the rationale for this proposed research is that understanding the mechanism supporting latency IIb infection by EBV may identify critical therapeutic targets for EBV-associated lymphomas and may inform our understanding of the temporal dynamics of EBV infection and the adaptive immune response to this ubiquitous orally-transmitted pathogen. We plan to test our hypothesis and complete the objectives outlined in this proposal through the following three specific aims: 1) Determine the mechanism regulating the switch in viral gene expression from early, EBNAs only (latency IIb), through late, EBNAs + LMPs (latency III), phases of primary tonsillar B-cell infection, 2) Determine the mechanism of early, NFκB-independent and late, NFκB- dependent EBV-infected tonsillar B-cell survival, and 3) Define the consequences of low LMP1/NFκB activity on EBV-infected B-cell peripheral blood and tonsillar B-cell immune recognition, activation, and killing b T cells.

 描述（由适用提供）：Epstein-Barr病毒（EBV）是一种γ-HERPESVIRUS，在全球范围内将近95％的成年人感染了伽马病毒。对病毒的潜在适应性免疫反应可防止大多数感染者的疾病。然而，免疫抑制（例如HIV-1感染期间）可以促进潜在的EBV驱动的B细胞淋巴瘤。我们的最终目标是定义EBV建立潜伏期的机制以及这些过程如何出现导致疾病的问题。在该提案中，我们旨在表征原发性扁桃体B细胞中EBV感染的新早期潜伏期，以及EBV介导的生存率和免疫逃避的机制对于建立和维持潜伏期储存库很重要。我们的中心假设是，在感染的前两周，EBV通过其EBV核抗原（EBNA）蛋白促进B细胞的增殖和存活。在感染期间后来，EBNA和潜在膜蛋白1（LMP1）是在永生状态下存活所必需的。我们建议，这种双相EBV潜伏基因表达程序的重要性是通过细胞毒性T细胞促进长期潜在受感染的细胞储存剂的有效播种来防止对EBV感染的B细胞的早期识别。我们已经根据临时病毒和宿主基因表达程序和宿主基因表达程序和生存机制的初步数据提出了中心假设 缺乏可欣赏的病毒LMP。重要的是，在与EBV相关的移植后和HIV淋巴瘤中观察到了这种潜伏期（IIB）。因此，这项拟议的研究的理由是，了解EBV支持潜伏期IIB感染的机制可能会确定与EBV相关淋巴瘤的关键治疗靶标，并可能告知我们对EBV感染的临时动态以及对这种普遍存在的口服口服疾病的临时动态的理解。我们计划通过以下三个具体目的来检验我们的假设，并完成本提案中概述的目标：1）确定从早期，仅EBNA（延迟IIB）到晚期到晚期，EBNAS + LMPS（潜伏期III）（延迟III）（延迟III），确定病毒基因表达的转换的机制，tonsillar b-cell Incection的阶段； EBV感染的扁桃体B细胞存活，3）定义LMP1/NFκB活性低对EBV感染的B细胞外周血和Tonsillar B细胞免疫识别，激活和杀死B T细胞的后果。