The synergistic contributions of EBV and malaria to the etiology of Burkitt lymphoma

EB 病毒和疟疾对伯基特淋巴瘤病因学的协同作用

• 批准号: 9887039
• 负责人: ROSEMARY ROCHFORD
• 金额: $ 67.37万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-12 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9887039
• 关键词: Acute; Africa; Africa South of the Sahara; African Burkitt' s lymphoma; B lymphoid malignancy; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; BACH2 gene; Binding; Biology; Blood Circulation; Burkitt Lymphoma; C-Myc Translocation; Cell Line; Cell Nucleus; Cells; Cellular biology; Characteristics; Child; Childhood; Clinical; Complex; Cytolysis; Cytoplasm; DNA; Data; Disease; Enzyme Activation; Epstein-Barr Virus latency; Epstein-Barr Virus-Related Malignant Neoplasm; Etiology; Event; Falciparum Malaria; Flow Cytometry; Frequencies; Genetic Transcription; Genome; Goals; Heme; Human Herpesvirus 4; IGH@ gene cluster; Individual; Infection; Kenya; Knowledge; Life; Ligands; Link; Lymphocyte; Lytic; Lytic Virus; MYC gene; Malaria; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Memory B-Lymphocyte; Modeling; Molecular; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Plasma Cells; Plasmodium falciparum; Population; Prevention; RNA; Research; Risk; Role; Sampling; Site; Structure of germinal center of lymph node; Testing; Time; Tonsil; Transcript; Variant; Viral; Viral Load result; Viremia; Virus; activation-induced cytidine deaminase; base; cancer cell; cytokine; design; hemozoin; high risk; improved; infected B cell; malaria infection; methylome; nanopore; pathogen; plasma cell differentiation; tool; transcription factor; tumorigenesis

PROJECT SUMMARY/ABSTRACT Epstein-Barr virus (EBV) was discovered over 50 years ago because of research into the etiology of endemic Burkitt lymphoma (BL). BL remains one of the most common and still frequently fatal pediatric cancers in sub- Saharan Africa. A second critical co-factor in the etiology of BL is repeated infection with Plasmodium falciparum (Pf) malaria. The exact cellular and molecular events that link these two pathogens to increase the risk for BL and drive the c-myc translocation characteristic of BL remain to be elucidated. Without this information, our understanding of the etiology of BL, a cancer called the Rosetta Stone for deciphering viral oncogenesis, remains incomplete. The overall goal of our research is to understand why children living in malaria endemic regions are at high risk for BL. Based on our studies in Kenya where we found children living in a malaria endemic region were infected with EBV early in life, had higher EBV viral loads over time and that malaria exposure has an independent effect on increasing EBV viral loads in children. Combined, these data point to an important role for malaria infection in dysregulating EBV latency. To account for the effects of malaria on EBV-infected B cells, we are proposing a variation of the GC model, termed the “Dysequilibrium model of EBV persistence.” In our model, the excess of heme released during malaria infection binds to the B cell transcription factor, Bach2 suppressing its activity. Release of Bach2 mediated suppression allows Blimp1 to orchestrate plasma cell differentiation. EBV would reactivate in terminally differentiated plasma cells resulting in viremia and an elevated population of secondarily infected B cells. An increased frequency of EBV- infected B cells in and of itself is not necessarily problematic but we have also observed high levels of the enzyme—activation induced deaminase (AID)—in peripheral blood mononuclear cells (PBMC) in children living in a malaria endemic region and dysregulation of AID expression in B cell subsets during acute malaria. The critical molecular event that defines BL is the translocation of the c-myc oncogene into the immunoglobulin heavy chain locus, an event mediated by AID. Moreover, we show in our preliminary data that BAFF synergizes with EBV to induce AID. Thus, the elevated population of latently infected B cells would be induced to express AID increasing the risk for the c-myc translocation. Utilizing lymphocytes analyzed ex vivo, EBV+ B cell lines, and in pediatric clinical samples from our field site in Kisumu, Kenya, we will test two key predictions based on our model. First, that release of excessive heme by lysis of RBC during malaria results in EBV reactivation in plasma cells and expansion of the latently infected B cell pool. Second, that increases in BAFF during malaria results in aberrant AID expression in EBV-positive B cells. Dysregulation of EBV persistence likely contributes not only to BL but also to other EBV-associated malignancies where co-factors are required for emergence of disease. Lessons learned from studying the etiology of BL could potentially be used for understanding the etiology of other EBV associated malignancies.

项目摘要/摘要 由于研究了内在的病因，因此在50年前发现了Epstein-Barr病毒（EBV）。 伯基特淋巴瘤（BL）。 BL仍然是亚属中最常见且仍然经常致命的小儿癌 撒哈拉非洲。 BL病因中的第二个临界副因素是用疟原虫重复感染 恶性疟疾（PF）疟疾。确切的细胞和分子事件，将这两种病原体联系起来增加 BL的风险和驱动C-MYC易位特征仍有待阐明。没有这个 信息，我们对BL病因的理解，一种称为Rosetta Stone的癌症，用于解密病毒 肿瘤发生，仍然不完整。我们研究的总体目标是了解为什么住在 疟疾内在区域有BL的高风险。根据我们在肯尼亚的研究，我们发现孩子们活着 在疟疾中，内在区域在生命的早期就感染了EBV，随着时间的流逝，EBV病毒负荷较高，并且 疟疾暴露对增加儿童的EBV病毒负荷有独立的影响。合并，这些数据 指出疟疾感染在失调EBV潜伏期中的重要作用。考虑到的影响 在EBV感染的B细胞上的疟疾，我们提出了GC模型的变化，称为“ Dysecilebibrium 在我们的模型中，疟疾感染期间释放的血红素的过量与B结合 细胞转录因子Bach2抑制其活性。 Bach2介导的抑制的释放允许Blimp1 编排浆细胞分化。 EBV将在终末分化的浆细胞中重新激活 导致病毒血症和继发感染B细胞升高。 EBV的频率增加 受感染的B细胞本身不一定有问题，但我们也观察到了高水平的 酶 - 激活诱导的脱氨酶（AID） - 在生活的儿童的外周血单核细胞（PBMC）中 在疟疾的疟疾区域和急性疟疾期间B细胞子集中辅助表达的失调。这 定义BL的关键分子事件是c-myc癌基因易位到免疫球蛋白 重链基因座，这是由援助介导的事件。此外，我们在初步数据中显示 与EBV协同诱导援助。那就是诱发升高的潜在感染B细胞的群体 表达援助增加了C-MYC易位的风险。利用分析过体内的淋巴细胞，EBV+ B 细胞系，以及来自肯尼亚基苏木现场现场的小儿临床样品，我们将测试两个关键的预测 基于我们的模型。首先，疟疾期间RBC释放过多血红素会导致EBV 浆细胞中的重新激活和潜在感染的B细胞库的扩展。其次，这增加了Baff 在疟疾期间会导致EBV阳性B细胞异常的辅助表达。 EBV持久性的失调 可能不仅有助于BL，还为需要EBV相关的恶性肿瘤做出贡献 出现疾病。从研究BL的病因中汲取的经验可能会用于 了解其他EBV相关的恶性肿瘤的病因。