Defining host mechanisms that restrict EBV lytic reactivation

定义限制 EBV 裂解再激活的宿主机制

基本信息

批准号：
10748051
负责人：
Lauren Haynes
金额：
$ 4.12万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748051
关键词：
Adult Area B-Cell Activation B-Cell Antigen Receptor B-Lymphocytes BZLF1 gene Benign Biology Cancer cell line Cell Communication Cell Death Cell Fraction Cell physiology Cells Clinical Clinical Trials DNA Damage Data Data Set EBV-associated disease Enzyme-Linked Immunosorbent Assay Epstein Barr Virus B lymphoma cell Epstein-Barr Virus-Related Malignant Neoplasm Equilibrium Future Gene Expression Gene Expression Profile Genes Genetic Goals HIV Herpesviridae Histone Deacetylase Inhibitor Host Defense Mechanism Human Human Herpesvirus 4 Hypoxia IL6 gene Immediate-Early Genes Immune Immunocompetent Immunologic Deficiency Syndromes In Vitro Individual Infection Infectious Mononucleosis Integration Host Factors Intercellular adhesion molecule 1 Interleukin 6 Receptor Interleukin-6 Knowledge Lead Life Life Cycle Stages Lymphoma Lytic Lytic Phase Lytic Virus Malignant Neoplasms Memory B-Lymphocyte NFKBIA gene Nature Neoadjuvant Therapy Oral cavity Oral mucous membrane structure Outcome Pathway interactions Patients Phase Phenotype Planets Population Process Production Productivity Proteins RNA Refractory Regulation Reporter Research Rest Role STAT3 gene Saliva Signal Transduction Site Sorting Stimulus Testing Time Transfection Viral Viral Genes Viral Genome Virus Virus Diseases Visualization Work cytokine effective therapy experimental study in vivo infected B cell large cell Diffuse non-Hodgkin&apos s lymphoma latent infection lytic gene expression neoplastic cell oral cavity epithelium oral infection particle plasma cell differentiation reactivation from latency recurrent infection response single-cell RNA sequencing stressor therapeutically effective transmission process tumorigenesis

项目摘要

ABSTRACT Epstein-Barr virus (EBV) is an extremely pervasive human herpesvirus, infecting approximately 95% of the global population by adulthood. EBV is transmitted through saliva and establishes infection in the oral cavity where it then establishes a latent infection for life in memory B cells. In most individuals this infection will remain benign, but EBV-associated diseases include infectious mononucleosis and cancers, more commonly in immune- compromised individuals. The balance between latent and lytic infection is under tight control and understanding the regulation of this process has broad implications for processes ranging from viral persistence in the oral mucosa to strategies to eliminate latently infected tumor cells. EBV reactivates in response to a diverse range of stressors including DNA damage, hypoxia, histone deacetylase inhibitors and activation of the B-cell receptor. A pervasive phenomenon, observed both in vitro and in vivo, is that cells have a heterogenous response to lytic induction stimuli. In a fraction of cells, the virus fully reactivates, while others remain completely refractory or only partially progress through the lytic cycle leading to an abortive infection. To better understand these cell fates after EBV lytic reactivation, my lab recently completed a single-cell RNA seq experiment of resting and reactivated EBV+ B lymphoma cells. We observed differential host gene expression patterns between refractory, abortive, and productive lytic cells. This included high expression of the known EBV restriction factors MYC and STAT3 in the refractory cells, but previously unknown markers of abortive cell populations: one characterized by elevated IL-6 receptor and the other defined by pro-survival signaling through the NFB pathway. Based on our single-cell data and prior studies, I hypothesize that an EBV induced DNA damage response leads to IL-6 production, which in turn promotes an abortive, antiviral state through the IL-6 receptor and ultimately pro- survival NFB signaling. In addition to defining mechanisms of host defense from EBV reactivation, this work also has important clinical ramifications as lytic induction therapies are currently in trials for EBV-associated malignancies. Understanding host factors that restrict successful lytic reactivation could lead to more effective therapeutic strategies in the future. Furthermore, these findings could have broad implications for how other herpesviruses reactivate and how latently infected cells communicate to regulate this process.

抽象的 EB 病毒 (EBV) 是一种极其普遍的人类疱疹病毒，感染全球约 95% 的人成年后 EB 病毒通过唾液传播并在口腔中形成感染。然后在记忆 B 细胞中建立终生的潜伏感染，在大多数个体中，这种感染将保持良性，但 EBV 相关疾病包括传染性单核细胞增多症和癌症，更常见于免疫性疾病潜伏感染和裂解感染之间的平衡受到严格控制和了解。这一过程的调节对病毒在口腔中的持续存在等过程具有广泛的影响。粘膜来消除潜伏感染的肿瘤细胞的策略，以响应不同范围的EBV重新激活。应激源包括 DNA 损伤、缺氧、组蛋白脱乙酰酶抑制剂和 B 细胞受体 A 的激活。在体外和体内观察到的普遍现象是细胞对裂解具有异质反应在一小部分细胞中，病毒完全重新激活，而其他细胞仍然完全难以抵抗或仅部分地完成裂解周期，导致感染失败。为了更好地了解这些细胞。为了了解 EBV 裂解再激活后的命运，我的实验室最近完成了一项静息和我们观察到难治性、难治性、再激活的 EBV+ B 淋巴瘤细胞之间存在差异的宿主基因表达模式。流产和生产裂解细胞这包括已知的 EBV 限制因子 MYC 和的高表达。 STAT3 存在于难治性细胞中，但以前未知的流产细胞群标记物：其特征在于根据我们的研究，IL-6 受体升高，而另一种受体则通过 NF+B 途径进行促生存信号传导。根据单细胞数据和之前的研究，我发现 EBV 诱导的 DNA 损伤反应会导致 IL-6 产生，进而通过 IL-6 受体促进流产的抗病毒状态，并最终促进除了定义宿主防御 EBV 重新激活的机制外，这项工作还包括生存 NFB 信号传导。也具有重要的临床影响，因为裂解诱导疗法目前正在针对 EBV 相关的试验中了解限制成功裂解重新激活的宿主因素可能会更有效。此外，这些发现可能对其他治疗策略产生广泛的影响。疱疹病毒重新激活以及潜伏感染细胞如何通过通讯来调节这一过程。