The impact of malaria and EBV on germinal center dynamics in the pathogenesis and evolution of endemic Burkitt lymphoma

疟疾和 EBV 对地方性伯基特淋巴瘤发病机制和进化中生发中心动态的影响

• 批准号: 518442780
• 负责人: Professorin Dr. Wiebke Hansen
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/518442780?language=en
• 关键词: impact; malaria; EBV; germinal; center

Coinfection with Plasmodium and EBV is essential for the pathogenesis of endemic Burkitt lymphoma (eBL), but the underlying molecular and cellular mechanisms contributed by each pathogen, are barely understood. Our preliminary data suggest that Plasmodium infection interferes with follicular helper T (Tfh) cell functions, thereby perturbing the germinal center (GC) environment. EBV provides a pro-survival effect to infected GC B cell clones, directly via the expression of molecules like the latent membrane protein 2A (LMP2A), but potentially also indirectly by interfering with GC B cell-Tfh cell selection processes. We assume that the coinfection with both pathogens can cause a premalignant condition, in which GC B cell (oligo-)clones expand independent of negative selection processes and independent of antigen clearance. Furthermore, as both infectious agents have been described to increase AID-mediated mutagenesis, we hypothesize that each pathogen influences the competition and evolution of pre-malignant clones until terminal transformation into eBL, e.g., upon MYC translocation. To investigate this, we will extend our analysis of Tfh cells and GC B cells at different timepoints during P. yoelii infection or SRBC immunization of WT mice and LMP2Atg mice to mimic EBV latency. Longitudinal BCR/TCR repertoire sequencing will be used to reveal the dynamics of clonal selection and outgrowth in the different experimental conditions, and RNA sequencing and functional analyses shall give insight into the deregulated pathways underlying the prolonged and perturbed GC reactions. The essential role of Tfh cells in eBL premalignancy will be confirmed by a conditional inducible Tfh cell knockout model. Finally, we aim to foster eBL lymphomagenesis by conditional MYC overexpression in GC B cells and determine the impact of Plasmodium- and/or EBV-(co)-infection on the growth dynamics and investigate the mutational landscape of developing eBL tumors in the different mouse models by exome sequencing.

疟原虫和EB病毒的混合感染是地方性Burkitt淋巴瘤(EBL)发病的重要因素，但两种病原体共同作用的分子和细胞机制尚不清楚。我们的初步数据表明，疟原虫感染干扰了滤泡辅助T细胞(TFH)的功能，从而扰乱了生发中心(GC)的环境。EBV可直接通过表达潜伏膜蛋白2A(LMP2A)等分子，间接干扰GC B细胞-Tfh细胞的选择过程，从而为感染的GC B细胞克隆提供促进生存的作用。我们推测，两种病原体的混合感染可导致癌前状态，即GC B细胞(寡核苷酸)克隆的扩增不依赖于阴性选择过程，也不依赖于抗原清除。此外，由于这两种病原体都被描述为增加了AID介导的突变，我们假设每种病原体都会影响癌前克隆的竞争和进化，直到最终转化为EBL，例如MYC易位。为了研究这一点，我们将扩展我们的分析，在约氏疟原虫感染或SRBC免疫的WT小鼠和LMP2Atg小鼠的不同时间点的Tfh细胞和GC B细胞，以模拟EBV潜伏期。纵向BCR/TCR谱带测序将用于揭示不同实验条件下克隆选择和生长的动力学，而RNA测序和功能分析将深入了解导致GC反应延长和扰动的解除调控的途径。TFH细胞在EBL癌前病变中的重要作用将被条件诱导的TFH细胞敲除模型所证实。最后，我们的目标是通过在GC B细胞中有条件地过度表达MYC来促进EBL淋巴肿瘤的发生，并确定疟原虫和/或EBV(联合)感染对生长动力学的影响，并通过外显子组测序来研究不同小鼠模型中发生EBL肿瘤的突变情况。