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

项目摘要/摘要 爱泼斯坦-巴尔病毒(EBV)是在50多年前因对地方性疾病病因学的研究而被发现的 Burkitt淋巴瘤(BL)。淋巴瘤仍然是最常见的、仍然经常致命的儿童癌症之一，在亚 撒哈拉非洲。BL病因学的第二个关键辅助因素是反复感染疟原虫 恶性疟疾(PF)。连接这两种病原体的确切的细胞和分子事件增加了 Bl的发病风险和c-myc易位特性仍有待阐明。如果没有这个 信息，我们对BL的病因学的理解，一种被称为Rosetta Stone的癌症，用于解密病毒 肿瘤的发生，仍未完成。我们研究的总体目标是了解为什么儿童生活在 疟疾流行区是疟疾流行的高危地区。根据我们在肯尼亚的研究，我们发现那里的儿童 在疟疾流行地区，在生命早期感染EBV的人，随着时间的推移有更高的EBV病毒载量， 疟疾暴露对儿童EBV病毒载量的增加具有独立的影响。综合来看，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EB病毒感染的B细胞上的疟疾，我们提出了一种GC模型的变体，称为“平衡失调” EBV持久化的典范。在我们的模型中，疟疾感染期间释放的过量血红素与B细胞结合。 细胞转录因子Bach2抑制其活性。释放Bach2介导的抑制允许Blimp1 来协调浆细胞分化。EB病毒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的B细胞数量增加。EB病毒感染频率的增加- 受感染的B细胞本身并不一定有问题，但我们也观察到高水平的 活体儿童外周血单个核细胞(PBMC)中酶激活诱导的脱氨酶(AID)- 在疟疾流行地区和急性疟疾期间B细胞亚群中AID表达的失调。这个 定义BL的关键分子事件是c-myc癌基因移位到免疫球蛋白中 重链基因，一种由AID介导的事件。此外，我们在初步数据中显示，BAFF 与EBV协同诱导AID。因此，潜伏感染的B细胞的数量将会增加 表达艾滋病会增加c-myc易位的风险。利用体外分析的淋巴细胞，EBV B 细胞系，以及我们在肯尼亚基苏木现场的儿科临床样本中，我们将测试两个关键预测 基于我们的模型。首先，疟疾期间红细胞裂解释放过量的血红素会导致EB病毒 浆细胞的重新激活和潜伏感染的B细胞池的扩大。第二，BAFF的增加 期间，疟疾导致EBV阳性B细胞中艾滋病病毒的异常表达。EBV持续性调节失调 可能不仅导致白血病，也可能导致其他需要辅助因素的EBV相关恶性肿瘤 为疾病的出现做准备。从白血病病因学研究中学到的经验教训可能被用于 了解其他EBV相关恶性肿瘤的病因。

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.