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.