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 转化的人类γ瘤病毒爱泼斯坦 - 巴尔病毒（EBV）和卡波西的肉瘤 - 相关的疱疹病毒（KSHV）与多种类型的恶性肿瘤的发展有关， 包括广泛的生发中心（GC）衍生的B细胞淋巴瘤。这些病毒已建立 通过感染的幼稚的B细胞和驱动这些细胞的终生潜在感染，独立于 抗原，利用GC反应增殖并分化为静止的记忆B细胞。那， 感染B细胞通过GC的转运对于γ掌病毒生物学至关重要。尽管如此， γ掌病毒操纵GC反应并贡献的特定机制 对GC衍生的B细胞淋巴瘤尚不完全了解。病毒编码的microRNA（miRNA） 由γ掌病毒使用来操纵受感染的细胞。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是 由于人类病毒的严格规格特异性，未知。鼠伽马广播病毒68 （MHV68，MUHV-4）与EBV和KSHV一般且具有病原体相关，并导致B细胞 淋巴瘤具有人类γ掌病毒恶性肿瘤的特征。我们最近有 证明了多功能宿主蛋白EWSR1的MHV68 miRNA miR-7-5p表达 （Ewing肉瘤断裂点蛋白1）促进GC B细胞的潜在感染。不过，值得注意的是 eWSR1在伽马梅氏病毒感染和GC B细胞生物学中的作用完全是 未知。在这里的工作中，我们将检验以下假设：EWSR1表达对于 生发中心B细胞增殖的扩增，定义了分子机制 EWSR1表达有助于生发中心B细胞扩张，并定义贡献 miR-7-5p介导的EWSR1表达对B细胞淋巴细胞的表达。