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

剖析 EBV 和恶性疟原虫在地方性伯基特淋巴瘤发病机制中的作用

基本信息

批准号：
10204966
负责人：
Micah A. Luftig
金额：
$ 64.82万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-14 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10204966
关键词：
Affect Affinity Africa African Burkitt&apos s lymphoma Antigens Area Automobile Driving B Cell Proliferation B-Cell Activation B-Cell Antigen Receptor B-Cell Development B-Cell Lymphomas B-Lymphocytes C-Myc Translocation CD8-Positive T-Lymphocytes Cell Line Cell Survival Cell surface Cells Characteristics Child Child Support Chromatin Chronic Clinical Coupled Data EBNA2 protein Epidemiology Epstein-Barr Virus Infections Epstein-Barr Virus latency Event Exposure to Gene Expression Generations Genes Genetic Transcription Goals Heavy-Chain Immunoglobulins Human Herpesvirus 4 IGH@ gene cluster Immune Immune response Immune system Immunity Immunologic Surveillance Immunosuppression In Vitro Individual Infection Large-Cell Immunoblastic Lymphoma Literature Lymphoma cell Lymphomagenesis MYC gene Maintenance Malaria Malignant Childhood Neoplasm Mediating Molecular Oncogenes Parasites Pathogenesis Pattern Plasmodium falciparum Publishing Receptor Signaling Regulation Risk Role Signal Transduction Specificity Surface Surface Immunoglobulins T-Lymphocyte T-Lymphocyte Subsets Testing Tumor Immunity Viral Viral Genome Virus Work activation-induced cytidine deaminase c-myc Genes cell transformation co-infection human pathogen humanized mouse in vivo infected B cell interest mouse model neoantigens neoplastic cell novel pathogen post-transplant pressure screening tumor tumorigenesis

项目摘要

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.

我们的长期目标是了解感染如何影响 B 细胞淋巴瘤的发展及其表面结合 B 细胞受体 (BCR) 的抗原特异性。了解 Pf 和 EBV 如何合作促进和维持 eBL 我们的中心假设是 Pf 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 特征的 IgH/c-Myc 易位，并且 eBL 肿瘤的维持受到 EBV 调节的支持肿瘤细胞存活和 T 细胞免疫的 Pf 改变是我们的中心假设的前提。根据文献和我们的初步数据，描述了 eBL 中 EBV 和 Pf 之间的相互作用。克隆地存在于 eBL 细胞中，表明其在肿瘤发生中的早期作用以及肿瘤发生的必要条件其次，疟疾大流行地区是已知的 eBL 热点地区，其发病率高达 100-100%。第三，B 细胞的 EBV 感染有效激活了的表达。激活诱导的胞苷脱氨酶 (AID)，这对于 BL 特征性 Ig/c-Myc 易位至关重要。 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 IgH 转录，因为 AID 需要 IgH 转录才能进入 IgH 基因座。 IgH/c-Myc 易位所需的，必须有一个额外的因素影响 EBV 感染的细胞，从而允许这种情况发生我们勇敢地说，Pf 以 EBV- 识别的抗原的形式提供了这种因子。我们认为 Pf 感染提供两种促有丝分裂信号来促进 B 细胞。增殖以及驱动 AID 介导的 BCR mat 亲和力的关键抗原，这异常导致 IgH/c-Myc 易位后，eBL 肿瘤必须承受来自 IgH/c-Myc 易位的强大压力。我们最近的工作表明免疫系统对病毒和肿瘤新抗原有很强的抑制作用。体内 Pf 感染对 CD8 T 细胞识别 EBV 和 eBL 的影响，我们认为支持肿瘤该提议的基本原理是了解 eBL 启动的分子机制。以及病毒和寄生虫混合感染的发病机制将为我们提供一个了解病毒和寄生虫共同感染的平台 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) 确定恶性疟原虫与EBV协同诱导B细胞增殖和肿瘤发生的作用， 2) 确定恶性疟原虫抗原作为 eBL 中 IgH/c-Myc 易位的关键触发因素的作用，以及 3) 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。