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B细胞淋巴瘤的发展如何受到感染的影响以及其表面结合的B细胞受体（BCR）的抗原特异性。该提议的目的是了解PF和EBV如何协调以促进和维护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识别为促进 BL-特征IGH/C-MYC易位，EBL肿瘤维持受EBV调节的支持 T细胞免疫的肿瘤细胞存活和PF改变。我们的中心假设以强大的理由为前提来自文献和我们的初步数据，这些数据表征了EBL中EBV和PF之间的相互作用。首先，EBV 在EBL细胞中存在克隆表明在肿瘤发生中的早期作用和在肿瘤中的需求维护。其次，疟疾全能区域是EBL的已知热点，其中率高达100-- 折叠高于低/无疟疾区域。第三，B细胞的EBV感染可能激活激活诱导的胞苷脱氨酶（AID），这对于BL-特征Ig/c-Myc易位至关重要。尽管 EBV潜在蛋白EBNA2在C-MYC基因促进表达的上游打开B细胞染色质，也抑制IGH转录。由于需要辅助才能进入IGH基因座，因此需要IGH IGH/C-MYC易位所需易位发生。我们假设PF以EBV-识别的抗原形式提供了这一因素感染的B细胞表面Ig。我们建议PF感染提供两个有丝分裂信号以促进B细胞增殖以及关键抗原驱动辅助介导的BCR亲和力成熟，异常导致 IGH/C-MYC易位。易位后，EBL肿瘤必须承受来自对病毒和肿瘤新抗原的免疫系统。我们最近的工作表明很强 PF感染在体内的影响对我们提出的EBV和EBL的CD8 T细胞识别支持肿瘤维护。该提议的理由是了解EBL启动的分子机制与病毒和寄生虫共感染相对于病毒和寄生虫感染的发病机理将为我们提供一个理解的平台 BCR特异性在B淋巴细胞化中的作用以及PF感染如何影响免疫外科手术支持维持肿瘤。我们计划通过追求以下三个具体目标来检验中心假设： 1）确定恶性疟原虫在与EBV合作诱导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易位的关键触发器的作用，并且 3）确定EBL肿瘤维持中EBV和恶性疟原虫免疫改变之间的相互作用。