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.

抽象的爱泼斯坦 - 巴尔病毒（EBV）是一种极普遍的人类疱疹病毒，感染了约95％的全球成年人的人口。 EBV通过唾液传播，并在其口腔中建立感染然后在记忆B细胞中建立潜在的生命感染。在大多数人中，这种感染将保持良性，但是与EBV相关的疾病包括传染性单核细胞增多症和癌症，更常见于免疫妥协的个人。潜在感染和裂解感受之间的平衡受到严格控制和理解该过程的调节对从口腔中的病毒持久性等过程具有广泛的影响粘膜与消除最近感染的肿瘤细胞的策略。 EBV响应于潜水范围的响应包括DNA损伤，缺氧，组蛋白脱乙酰基酶抑制剂和B细胞受体的激活。一个在体外和体内观察到的普遍现象是细胞对裂解的异源反应诱导刺激。在一小部分细胞中，病毒完全重新激活，而其他病毒则完全难治性或仅部分通过裂解周期进展，导致流产感染。更好地了解这些细胞 EBV裂解重新激活后的命运，我的实验室最近完成了一个单细胞RNA SEQ实验的静止和重新激活EBV+ B淋巴瘤细胞。我们观察到难治性差异宿主基因表达模式流产和产物裂解细胞。这包括已知的EBV限制因素MYC和难治性细胞中的STAT3，但以前未知的流入细胞群体标记：一种以 IL-6受体升高，另一种是通过NFB途径促生存的信号传导定义的。基于我们单细胞数据和先前的研究，我假设EBV诱导的DNA损伤响应导致IL-6 生产又通过IL-6受体促进了堕胎的抗病毒状态，并最终促进生存NFB信号传导。除了定义EBV重新激活的宿主防御机制外，这项工作还由于裂解诱导疗法目前正在试用EBV相关的试验中，还具有重要的临床影响恶性肿瘤。了解限制成功裂解重新激活的宿主因素可能会导致更有效将来的治疗策略。此外，这些发现可能对其他方式具有广泛的影响疱疹病毒重新激活，以及受感染的细胞如何传播以调节该过程。