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.

项目总结/摘要 EB病毒（EBV）是50多年前发现的，因为对地方性流行病的病因学进行了研究。 伯基特淋巴瘤（BL）。BL仍然是亚健康儿童中最常见且仍经常致命的儿科癌症之一。 撒哈拉非洲。BL病因学中的第二个关键辅助因素是反复感染疟原虫 恶性疟原虫（Pf）疟疾。将这两种病原体联系起来以增加 BL的风险和驱动BL的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，一种被称为罗塞塔石碑的癌症，用于破译病毒 肿瘤发生，仍然不完全。我们研究的总体目标是了解为什么生活在 疟疾流行区是BL的高风险区。根据我们在肯尼亚的研究，我们发现 在疟疾流行地区，在生命早期感染EBV，随着时间的推移，EBV病毒载量较高， 疟疾暴露对儿童EBV病毒载量的增加具有独立影响。综合起来，这些数据 指出疟疾感染在EBV潜伏期失调中的重要作用。之影响入账 疟疾对EB病毒感染的B细胞的影响，我们提出了GC模型的一个变体，称为“失衡 EB病毒持久性模型。”在我们的模型中，疟疾感染期间释放的过量血红素与B结合 细胞转录因子Bach 2抑制其活性。Bach 2介导的抑制的释放允许Blimp 1 来协调浆细胞分化。EBV在终末分化的浆细胞中重新激活 导致病毒血症和继发性感染的B细胞群升高。EB病毒的频率增加- 感染的B细胞本身并不一定有问题，但我们也观察到高水平的 酶激活诱导的脱氨酶（AID）-在生活的儿童外周血单个核细胞（PBMC） 在疟疾流行区和急性疟疾期间B细胞亚群中AID表达失调。的 定义BL的关键分子事件是c-myc癌基因易位到免疫球蛋白中 重链基因座，由AID介导的事件。此外，我们在初步数据中表明，BAFF 与EBV协同诱导AID。因此，将诱导潜伏感染的B细胞群体的升高 表达AID增加了c-myc易位的风险。利用离体分析的淋巴细胞，EBV+ B 细胞系，以及来自肯尼亚基苏穆的儿科临床样本，我们将测试两个关键的预测 基于我们的模型。首先，疟疾期间红细胞溶解释放过量血红素导致EBV 浆细胞中的再活化和潜伏感染的B细胞池的扩增。第二，BAFF的增加 在疟疾期间，导致EBV阳性B细胞中异常的AID表达。EBV持续性失调 可能不仅导致BL，还导致其他需要辅助因子的EBV相关恶性肿瘤 for emergency出现of disease疾病.从BL病因学研究中获得的经验教训可能用于 了解其他EBV相关恶性肿瘤的病因。