Ma Shi-Dong, Tsai Ming-Han, Romero-Masters James C, Ranheim Erik A, Huebner Shane M, Bristol Jillian A, Delecluse Henri-Jacques, Kenney Shannon C
Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Deutsches Krebsforschungszentrum and Inserm, Heidelberg, Germany.
J Virol. 2017 Mar 13;91(7). doi: 10.1128/JVI.01928-16. Print 2017 Apr 1.
Epstein-Barr virus (EBV) infection is associated with B cell lymphomas in humans. The ability of EBV to convert human B cells into long-lived lymphoblastoid cell lines (LCLs) requires the collaborative effects of EBNA2 (which hijacks Notch signaling), latent membrane protein 1 (LMP1) (which mimics CD40 signaling), and EBV-encoded nuclear antigen 3A (EBNA3A) and EBNA3C (which inhibit oncogene-induced senescence and apoptosis). However, we recently showed that an LMP1-deleted EBV mutant induces B cell lymphomas in a newly developed cord blood-humanized mouse model that allows EBV-infected B cells to interact with CD4 T cells (the major source of CD40 ligand). Here we examined whether the EBV LMP2A protein, which mimics constitutively active B cell receptor signaling, is required for EBV-induced lymphomas in this model. We find that the deletion of LMP2A delays the onset of EBV-induced lymphomas but does not affect the tumor phenotype or the number of tumors. The simultaneous deletion of both LMP1 and LMP2A results in fewer tumors and a further delay in tumor onset. Nevertheless, the LMP1/LMP2A double mutant induces lymphomas in approximately half of the infected animals. These results indicate that neither LMP1 nor LMP2A is absolutely essential for the ability of EBV to induce B cell lymphomas in the cord blood-humanized mouse model, although the simultaneous loss of both LMP1 and LMP2A decreases the proportion of animals developing tumors and increases the time to tumor onset. Thus, the expression of either LMP1 or LMP2A may be sufficient to promote early-onset EBV-induced tumors in this model. EBV causes human lymphomas, but few models are available for dissecting how EBV causes lymphomas in the context of a host immune response. We recently used a newly developed cord blood-humanized mouse model to show that EBV can cooperate with human CD4 T cells to cause B cell lymphomas even when a major viral transforming protein, LMP1, is deleted. Here we examined whether the EBV protein LMP2A, which mimics B cell receptor signaling, is required for EBV-induced lymphomas in this model. We find that the deletion of LMP2A alone has little effect on the ability of EBV to cause lymphomas but delays tumor onset. The deletion of both LMP1 and LMP2A results in a smaller number of lymphomas in infected animals, with an even more delayed time to tumor onset. These results suggest that LMP1 and LMP2A collaborate to promote early-onset lymphomas in this model, but neither protein is absolutely essential.
爱泼斯坦-巴尔病毒（EBV）感染与人类B细胞淋巴瘤有关。EBV将人类B细胞转化为长寿淋巴母细胞系（LCLs）的能力需要EBNA2（劫持Notch信号）、潜伏膜蛋白1（LMP1）（模拟CD40信号）以及EBV编码的核抗原3A（EBNA3A）和EBNA3C（抑制癌基因诱导的衰老和凋亡）的协同作用。然而，我们最近发现，在一种新开发的脐血人源化小鼠模型中，一种缺失LMP1的EBV突变体可诱导B细胞淋巴瘤，该模型使受EBV感染的B细胞能够与CD4 T细胞（CD40配体的主要来源）相互作用。在此，我们研究了在该模型中，模拟组成型活化B细胞受体信号的EBV LMP2A蛋白对于EBV诱导淋巴瘤是否必要。我们发现，缺失LMP2A会延迟EBV诱导淋巴瘤的发病，但不影响肿瘤表型或肿瘤数量。同时缺失LMP1和LMP2A会导致肿瘤数量减少且肿瘤发病进一步延迟。尽管如此，LMP1/LMP2A双突变体在大约一半的受感染动物中诱导出淋巴瘤。这些结果表明，在脐血人源化小鼠模型中，LMP1和LMP2A对于EBV诱导B细胞淋巴瘤的能力都不是绝对必需的，尽管同时缺失LMP1和LMP2A会降低发生肿瘤的动物比例并延长肿瘤发病时间。因此，在该模型中，LMP1或LMP2A的表达可能足以促进EBV诱导的早期肿瘤发生。EBV可导致人类淋巴瘤，但在宿主免疫反应背景下剖析EBV如何引发淋巴瘤的模型却很少。我们最近使用一种新开发的脐血人源化小鼠模型表明，即使主要的病毒转化蛋白LMP1缺失，EBV也能与人类CD4 T细胞协同导致B细胞淋巴瘤。在此，我们研究了在该模型中，模拟B细胞受体信号的EBV蛋白LMP2A对于EBV诱导淋巴瘤是否必要。我们发现，单独缺失LMP2A对EBV引发淋巴瘤的能力影响不大，但会延迟肿瘤发病。同时缺失LMP1和LMP2A会使受感染动物中的淋巴瘤数量减少，肿瘤发病时间延迟更久。这些结果表明，在该模型中LMP1和LMP2A协同促进早期淋巴瘤发生，但两种蛋白都不是绝对必需的。
