Epstein-Barr virus and B-cell co-opted functions of the endogenous retrovirus envelope protein, Syncytin-1

Epstein-Barr 病毒和 B 细胞共同选择内源性逆转录病毒包膜蛋白 Syncytin-1 的功能

基本信息

批准号：
10490258
负责人：
Tiffany Frey
金额：
$ 4.32万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-13 至 2023-09-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10490258
关键词：
Antiviral Agents Apoptosis Autoimmune Diseases Azacitidine B Cell Proliferation B-Cell Lymphomas B-Lymphocyte Subsets B-Lymphocytes Binding Breast Burkitt Lymphoma Cancer Etiology Cell Cycle Cell Line Cell Proliferation Cell Survival Cells Cellular biology Colorectal Coupled DNA Methyltransferase Inhibitor Development Diffusion Down-Regulation Elements Embryonic Development Endogenous Retroviruses Endometrial Carcinoma Epigenetic Process Epithelial Cells Epstein-Barr Virus Infections Epstein-Barr Virus latency Epstein-Barr Virus-Related Malignant Neoplasm Evolution Fetus Flow Cytometry Gene Expression Genes Genetic Goals Herpesviridae Histone Deacetylase Inhibitor Hodgkin Disease Hormones Human Human Biology Human Genome Human Herpesvirus 4 Human Herpesvirus 8 Immune Evasion Immunocompromised Host Individual Infection Infectious Mononucleosis Inflammatory Kidney Life Link Lymphoproliferative Disorders Lytic Lytic Phase Lytic Virus Malignant Epithelial Cell Malignant Neoplasms Mediating Memory B-Lymphocyte Modeling Morbidity - disease rate Mothers Mutagenesis Nerve Degeneration Nutrient Oncolytic Oropharyngeal Ovarian Pathology Peripheral Blood Mononuclear Cell Phase Phenotype Placenta Placentation Play Population Prevention strategy Preventive Primary Infection Production Protein Biosynthesis Proteins Regulation Retrovirus Proteins Risk Role Signal Pathway Sodium Butyrate Source Stomach Carcinoma Syncytiotrophoblast System Tertiary Protein Structure Therapeutic Transcript Vaccines Viral Genes Virus Virus Diseases Western Blotting cell transformation defined contribution env Gene Products epigenetic silencing experience gammaherpesvirus human disease infected B cell insight leukemia/lymphoma lymphoblastoid cell line lytic replication mTOR Signaling Pathway metaplastic cell transformation mortality mutant pathogen syncytin therapeutic target tool trophoblast virus related cancer

项目摘要

Project Summary Aberrant expression of human endogenous retroviruses (HERVs) has been associated with enhanced pathology in a number of cancers and autoimmune diseases (1, 2). One of these HERV elements is the protein Syncytin- 1, encoded by the ERVW1 gene, and is essential for placental development. Although these elements are epigenetically silenced after embryonic development, exogenous viral infections, such as Epstein-Barr virus (EBV), have been linked to enhanced expression of HERVs (3-7). EBV, a gamma-herpesvirus, is the cause of infectious mononucleosis and associated with a number of cancers including Burkitt lymphoma (BL), nasopharyngeal cell carcinoma, Hodgkin’s disease, and other lymphoproliferative diseases. With no vaccine or antiviral drug available, EBV is an important pathogen to study. Primary infection with EBV begins with its attachment, fusion, and entry into oropharyngeal epithelial cells. EBV then spreads to memory B cells where it persists for the life of the host, generally in a latent state. During latency, only a small subset of EBV genes are expressed (8). Periodically, EBV undergoes lytic activation in a subset of B cells to persist in the population. Importantly, lytic activation of EBV not only increases risks for development of EBV-related cancers, particularly in immunocompromised hosts, but may also be exploited to treat EBV-associated cancers in an approach known as oncolytic therapy. Lytic activation is characterized by the expression of over 80% of EBV genes, many of which serve in immune evasion, regulation of apoptosis, and blockade of host protein synthesis. This latter phenomenon results in the downregulation of most host genes, known as global host shutoff, and the preferential expression of viral genes (9). Despite global host shutoff, I find that the HERV element ERVW1, which encodes Syncytin-1, increases in both transcript and protein levels during lytic activation of EBV in infected B cells. This, coupled with the fact that similar epigenetic mechanisms silence both HERVs and latent EBV, leads me to predict that EBV may spare and/or activate Syncytin-1 for a specific purpose during lytic replication. This study will elucidate the functions of Syncytin-1 during EBV infection of B cells. It will reveal why Syncytin-1 The study will further characterize the consequences of Syncytin-1 depletion and mutagenesis on B cell biology as well as the interactions of Syncytin-1 broadly with B cell proteins and specifically with the PI3K/Akt/mTOR signaling pathway, known to trigger EBV lytic replication, B cell survival, and proliferation. The proposed studies are aimed at revealing mechanisms governing the role of Syncytin-1 in lymphoproliferative diseases and B cell lymphomas. is upregulated despite host cell shutoff by delineating Syncytin-1’s influence during the EBV lytic cycle. Hypothesis: I hypothesize that Syncytin-1 is selectively spared by EBV because it has a role in potentiating lytic replication. I also hypothesize that Syncytin-1 plays a role in B cell biology by promoting cell proliferation. Aim 1: Define the contribution of Syncytin-1 to Epstein-Barr virus lytic cycle. Aim 2: Determine the functional role of Syncytin-1 in B cell proliferation.

项目概要人内源性逆转录病毒 (HERV) 的异常表达与病理学增强有关在许多癌症和自身免疫性疾病中 (1, 2)，这些 HERV 元件之一是蛋白质 Syncytin-。 1，由 ERVW1 基因编码，对于胎盘发育至关重要。胚胎发育、外源病毒感染（例如 Epstein-Barr 病毒）后表观遗传沉默 (EBV) 与 HERV 表达增强有关 (3-7) EBV（一种 γ-疱疹病毒）是导致这种疾病的原因。传染性单核细胞增多症并与多种癌症相关，包括伯基特淋巴瘤 (BL)、鼻咽细胞癌、霍奇金病和其他淋巴组织增生性疾病没有疫苗或疫苗。随着抗病毒药物的出现，EBV 是研究 EBV 原发感染的重要病原体。 EBV 附着、融合并进入口咽上皮细胞，然后扩散到记忆 B 细胞。在宿主的一生中持续存在，通常处于潜伏状态，在潜伏期，只有一小部分 EBV 基因处于潜伏状态。 EBV 会定期在 B 细胞亚群中进行裂解激活，从而在群体中持续存在。重要的是，EBV 的裂解激活不仅增加发生 EBV 相关癌症的风险，特别是在免疫功能低下的宿主中，但也可用于以已知的方法治疗 EBV 相关癌症溶瘤疗法的特点是超过 80% 的 EBV 基因表达，其中许多基因表达。其作用在于免疫逃避、细胞凋亡的调节以及宿主蛋白质合成的阻断。这种现象导致大多数宿主基因下调，称为全局宿主关闭，并且优先尽管宿主全局关闭，但我发现编码 HERV 的 ERVW1 元件仍然存在。 Syncytin-1，在感染 B 细胞中 EBV 裂解激活过程中转录物和蛋白质水平增加。再加上类似的表观遗传机制会使 HERV 和潜在 EBV 沉默，这让我预测 EBV 在裂解复制过程中可能出于特定目的保留和/或激活 Syncytin-1。这项研究将阐明 Syncytin-1 在 EBV 感染 B 细胞过程中的功能，并揭示 Syncytin-1 的作用。研究将进一步表征 Syncytin-1 耗竭和诱变对 B 细胞生物学以及 Syncytin-1 与 B 细胞蛋白的广泛相互作用，特别是与 PI3K/Akt/mTOR 信号传导的相互作用已知可触发 EBV 裂解复制、B 细胞存活和增殖。揭示 Syncytin-1 在淋巴增殖性疾病和 B 细胞淋巴瘤中的作用机制。尽管宿主细胞关闭，但通过描述 Syncytin-1 在 EBV 裂解周期中的影响，该蛋白仍上调。假设：我老公，Syncytin-1 选择性地不受 EBV 的影响，因为它具有增强裂解的作用我还研究了 Syncytin-1 通过促进细胞增殖在 B 细胞生物学中发挥的作用。目标 1：确定 Syncytin-1 对 Epstein-Barr 病毒裂解周期的贡献。目标 2：确定 Syncytin-1 在 B 细胞增殖中的功能作用。