Defining host mechanisms that restrict EBV lytic reactivation

定义限制 EBV 裂解再激活的宿主机制

• 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
• 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' 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

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.

摘要 爱泼斯坦-巴尔病毒(EBV)是一种极其普遍的人类疱疹病毒，感染全球约95%的 按成年期划分的人口。EB病毒通过唾液传播，并在口腔内造成感染，在那里 然后在记忆B细胞中建立一种潜在的生命感染。在大多数人中，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，更常见的是免疫性- 受威胁的人。潜伏感染和裂解感染之间的平衡得到了严格的控制和理解 这一过程的调节对于从口腔中的病毒持续存在的过程具有广泛的影响 从粘膜到消除潜伏感染的肿瘤细胞的策略。EBV重新激活以应对一系列不同的 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细胞有异质性反应。 感应刺激。在一小部分细胞中，病毒完全重新激活，而另一些细胞则保持完全难治或 在溶解周期中只有部分进展，导致流产感染。为了更好地了解这些细胞 命运在EBV裂解重新激活后，我的实验室最近完成了一项单细胞RNA序列实验，即静息和 重新激活EBV+B淋巴瘤细胞。我们观察到不同的宿主基因在难治性、 流产的、多产的裂解细胞。这包括已知的EBV限制因子MYC和 STAT3在难耐细胞中，但以前未知的败育细胞群体的标记：一种特征为 IL-6受体升高和另一种是通过NFB途径促进生存信号定义的。基于我们的 单细胞数据和以前的研究，我假设EBV诱导的DNA损伤反应导致IL-6 产生，进而通过IL-6受体促进流产的抗病毒状态，最终促进- 存活核因子B信号转导。除了定义宿主防御EBV重新激活的机制外，这项工作还 也有重要的临床影响，因为溶解诱导疗法目前正在试验EBV相关的 恶性肿瘤。了解限制成功裂解再激活的宿主因素可能会导致更有效的 未来的治疗策略。此外，这些发现可能会对其他 疱疹病毒重新激活，以及潜伏感染的细胞如何沟通来调节这一过程。