Gammaherpesvirus miRNA suppression of EWSR1 in GC B cell infection and lymphomagenesis

伽马疱疹病毒 miRNA 对 GC B 细胞感染和淋巴瘤发生中 EWSR1 的抑制

• 批准号: 10665619
• 负责人: Scott A. Tibbetts
• 金额: $ 44.75万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665619
• 关键词: Antigens; Automobile Driving; B-Cell Lymphomas; B-Lymphocytes; Binding; Biological; Biology; Cells; Cellular biology; Chimeric Proteins; DNA Damage; Dangerousness; Development; Disease; Event; Ewings sarcoma; Foundations; Genetic; Genetic Recombination; Goals; HIV; Herpesviridae; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune response; Immunocompromised Host; Infection; Link; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant Neoplasms; Mediating; Memory B-Lymphocyte; Messenger RNA; MicroRNAs; Molecular; Mus; Pathogenicity; Process; Proliferating; Proteins; RNA Splicing; RNA-Binding Protein EWS; RNA-Binding Proteins; Reaction; Regulation; Repression; Rest; Role; Species Specificity; Structure of germinal center of lymph node; System; Testing; Transcription Coactivator; Transcription Repressor; Untranslated RNA; Validation; Viral; Viral Physiology; Viral reservoir; Virus; Work; biological adaptation to stress; defined contribution; gammaherpesvirus; in vivo; infected B cell; latent infection; lymphoid structures; mRNA Stability; novel; prevent; rational design; tumorigenesis

Summary The transforming human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma- associated herpesvirus (KSHV) are linked to the development of multiple types of malignancies, including a wide range of germinal center (GC)-derived B cell lymphomas. These viruses establish lifelong latent infections in B cells by infecting naïve B cells and driving those cells, independent of antigen, to utilize GC reactions to proliferate and differentiate into resting memory B cells. Thus, the transit of infected B cells through the GC is critical to gammaherpesvirus biology. Despite this, the specific mechanisms by which gammaherpesviruses manipulate GC reactions and contribute to GC-derived B cell lymphomas are not fully understood. Virus-encoded microRNAs (miRNAs) are employed by gammaherpesviruses to manipulate infected cells. Importantly though, the specific in vivo functions and biological relevance of these miRNAs are almost completely unknown due to the strict species specificity of the human viruses. Murine gammaherpesvirus 68 (MHV68, MuHV-4) is genetically and pathogenically related to EBV and KSHV, and causes B cell lymphomas with features of human gammaherpesvirus malignancies. We have recently demonstrated that MHV68 miRNA miR-7-5p repression of the multifunctional host protein EWSR1 (Ewing sarcoma breakpoint protein 1) promotes latent infection of GC B cells. Notably though, the roles of EWSR1 in both gammaherpesvirus infection and GC B cell biology are completely unknown. In work here, we will test the hypothesis that EWSR1 repression is critical for proliferative expansion of germinal center B cells, define the molecular mechanism by which EWSR1 repression contributes to germinal center B cell expansion, and define the contribution of miR-7-5p-mediated EWSR1 repression to B cell lymphomagenesis.

概括 转化人类伽马疱疹病毒、EB 病毒 (EBV) 和卡波西肉瘤 相关疱疹病毒（KSHV）与多种恶性肿瘤的发生有关， 包括多种生发中心 (GC) 衍生的 B 细胞淋巴瘤。这些病毒建立 通过感染幼稚 B 细胞并驱动这些细胞，实现 B 细胞的终生潜伏感染，独立 抗原，利用 GC 反应增殖并分化为静息记忆 B 细胞。因此， 受感染的 B 细胞通过 GC 的转运对于伽马疱疹病毒生物学至关重要。尽管如此， 伽马疱疹病毒操纵 GC 反应并做出贡献的具体机制 GC 衍生的 B 细胞淋巴瘤尚未完全了解。病毒编码的 microRNA (miRNA) 被伽玛疱疹病毒用来操纵受感染的细胞。但重要的是， 这些 miRNA 的特定体内功能和生物学相关性几乎完全 由于人类病毒严格的物种特异性，未知。鼠伽马疱疹病毒 68 （MHV68、MuHV-4）与 EBV 和 KSHV 具有遗传和致病性相关，并引起 B 细胞 具有人类伽马疱疹病毒恶性肿瘤特征的淋巴瘤。我们最近有 证明 MHV68 miRNA miR-7-5p 抑制多功能宿主蛋白 EWSR1 （尤文肉瘤断点蛋白 1）促进 GC B 细胞的潜伏感染。但值得注意的是， EWSR1 在伽马疱疹病毒感染和 GC B 细胞生物学中的作用完全 未知。在此工作中，我们将检验以下假设：EWSR1 抑制对于 生发中心 B 细胞的增殖扩张，定义了其分子机制 EWSR1 抑制有助于生发中心 B 细胞扩增，并定义了其贡献 miR-7-5p 介导的 EWSR1 抑制对 B 细胞淋巴瘤发生的影响。