Dissecting the role of EBV and P. falciparum in endemic Burkitt lymphoma pathogenesis

我们的长期目标是了解感染是如何影响B细胞淋巴瘤的发展的 以及其表面结合的B细胞受体(BCR)的抗原特异性。这项建议的目标是 了解PF和EBV如何合作促进和维护EBL。我们的中心假设是肺炎支原体感染 促进EBV介导的B细胞增殖，PF抗原被EBV感染的BCR识别，促进 Bl-特异性IgH/c-Myc易位，EBL肿瘤维持由EBV调节 肿瘤细胞存活与T细胞免疫功能的变化。我们的中心假设是以强有力的理由为前提的 从文献和我们的初步数据描述EBV和PF在EBL中的相互作用。第一，EB病毒 在EBL细胞中克隆性存在，提示在肿瘤发生的早期作用和在肿瘤中的需要 维修。其次，疟疾全流行地区是已知的EBL热点，发病率高达100%- 比低/无疟疾地区高出一倍。第三，EB病毒感染B细胞可有效激活 激活诱导型胞苷脱氨酶(AID)，它是BL型Ig/c-Myc易位的关键。而当 EBV潜伏蛋白EBNA2打开c-Myc基因上游的B细胞染色质促进表达，它还 抑制高转录率。由于AID需要IgH转录才能获得IgH基因座，因此 是IgH/c-Myc易位所必需的，另一个因素肯定是影响EBV感染的细胞，从而允许这一点 发生移位。我们假设，PF以EBV识别的抗原形式提供这种因子- 感染B细胞表面免疫球蛋白。我们认为，PF感染提供了促进B细胞增殖的有丝分裂信号 增殖以及驱动AID介导的BCR亲和力成熟的关键抗原，这会异常地导致 IgH/c-Myc易位。移位后，EBL肿瘤必须经受住来自 针对病毒和肿瘤新抗原的免疫系统。我们最近的工作表明了一种强烈的抑制 PF体内感染对CD8T细胞识别EBV和EBL的影响 维修。这一建议的基本原理是理解EBL启动的分子机制 与病毒和寄生虫混合感染的致病机制将为我们提供一个了解 BCR特异性在B淋巴瘤病中的作用以及PF感染如何影响免疫监测 支持肿瘤维护。我们计划通过追求以下三个具体目标来检验我们的中心假设： 1)确定恶性疟原虫在与EBV协同诱导B细胞增殖和肿瘤发生中的作用， 2)确定恶性疟原虫抗原在EBL中作为IgH/c-Myc易位的关键触发因素的作用，以及 3)探讨EBV与恶性疟原虫免疫变化在EBL肿瘤维持中的相互作用。

Our long-term goal is to understand how the development of B-cell lymphomas is influenced by infection and the antigen specificity of their surface-bound B-cell receptors (BCR). The objective in this proposal is to understand how Pf and EBV cooperate to promote and maintain eBL. It is our central hypothesis that Pf infection promotes EBV-mediated B-cell proliferation, Pf antigens are recognized by the EBV-infected BCR promoting the BL-characteristic IgH/c-Myc translocation, and that eBL tumor maintenance is supported by EBV regulation of tumor cell survival and Pf alteration of T-cell immunity. Our central hypothesis is premised on strong rationale from the literature and our preliminary data characterizing the interplay between EBV and Pf in eBL. First, EBV is clonally present in eBL cells suggesting both an early role in tumorigenesis and a requirement in tumor maintenance. Second, malaria holoendemic areas are known hotspots for eBL where rates are as much as 100- fold higher than in low/no malarial regions. Third, EBV infection of B cells potently activates expression of activation-induced cytidine deaminase (AID), which is critical for BL-characteristic Ig/c-Myc translocations. While the EBV latent protein EBNA2 opens B-cell chromatin upstream of the c-Myc gene promoting expression, it also suppresses IgH transcription. Since IgH transcription is required for AID to gain access to the IgH locus and is required for the IgH/c-Myc translocation, an additional factor must be affecting EBV-infected cells allowing this translocation to occur. We hypothesize that Pf provides this factor in the form of antigen recognized by the EBV- infected B-cell surface Ig. We propose that Pf infections provide both mitogenic signals to promote B-cell proliferation as well as critical antigens driving AID-mediated BCR affinity maturation, which aberrantly leads to the IgH/c-Myc translocation. Following the translocation, eBL tumors must withstand strong pressure from the immune system against both the virus and tumor neoantigens. Our recent work indicates a strong suppressive influence of Pf infection in vivo on CD8 T-cell recognition of EBV and eBL that we propose supports tumor maintenance. The rationale for this proposal is that understanding the molecular mechanisms of eBL initiation and pathogenesis vis-à-vis viral and parasite co-infection will provide us with a platform for understanding the role of BCR specificity in B lymphomagenesis as well as how Pf infection influences immune surveillance to support tumor maintenance. We plan to test our central hypothesis by pursuing the following three specific aims: 1) to determine the role of P. falciparum in collaborating with EBV to induce B-cell proliferation and tumorigenesis, 2) to determine the role of P. falciparum antigens as the critical trigger of the IgH/c-Myc translocation in eBL, and 3) to determine the interplay between EBV and P. falciparum immune alterations in eBL tumor maintenance.