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

我们的长期目标是了解B细胞淋巴瘤的发展是如何受到感染的影响 及其表面结合B细胞受体（BCR）的抗原特异性。这项建议的目的是 了解Pf和EBV如何合作促进和维持eBL。我们的中心假设是， 促进EBV介导的B细胞增殖，Pf抗原被EBV感染的BCR识别，促进B细胞增殖。 BL-特征性IgH/c-Myc易位，并且eBL肿瘤维持受到EBV调节的支持， 肿瘤细胞存活和T细胞免疫的Pf改变。我们的中心假设是建立在强有力的理论基础上的 从文献和我们的初步数据表征EBV和Pf之间的相互作用在eBL。首先，EBV 克隆性存在于eBL细胞中，表明在肿瘤发生中的早期作用和肿瘤发生中的需要 上维护其次，疟疾全流行区是已知的eBL热点，其发病率高达100- 比低疟疾/无疟疾地区高一倍。第三，B细胞的EBV感染有效地激活了 活化诱导的胞苷脱氨酶（AID），其对于BL-特征性IG/c-Myc易位至关重要。而 EBV潜伏蛋白EBNA 2打开c-Myc基因上游的B细胞染色质，促进表达，它还 抑制IgH转录。由于AID需要IgH转录才能进入IgH基因座， IgH/c-Myc易位所需的，一个额外的因素必须影响EBV感染的细胞，使这一点 translocation发生。我们假设Pf以EBV识别的抗原形式提供该因子， 感染B细胞表面IG。我们认为，Pf感染提供了促有丝分裂信号，促进B细胞增殖， 增殖以及驱动艾滋病介导的BCR亲和力成熟的关键抗原，这异常地导致 IgH/c-Myc易位。易位后，eBL肿瘤必须承受来自肿瘤细胞的强大压力。 免疫系统抵抗病毒和肿瘤新抗原。我们最近的研究表明 体内Pf感染对CD 8 T细胞识别EBV和eBL影响，我们提出支持肿瘤 上维护这一建议的基本原理是，了解eBL启动的分子机制， 以及病毒和寄生虫共感染的发病机制将为我们提供一个了解 BCR特异性在B淋巴瘤发生中的作用以及Pf感染如何影响免疫监视， 支持肿瘤维持。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)为了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作为eBL中IgH/c-Myc易位的关键触发物的作用，和 3)以确定EBV和恶性疟原虫免疫改变在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.