Martin Heather J, Lee Jae Myun, Walls Dermot, Hayward S Diane
Johns Hopkins School of Medicine, Bunting-Blaustein Building CRB308, 1650 Orleans Street, Baltimore, MD 21231-1000, USA.
J Virol. 2007 Sep;81(18):9748-58. doi: 10.1128/JVI.01122-07. Epub 2007 Jul 3.
Epstein-Barr virus (EBV) infection of primary B cells causes B-cell activation and proliferation. Activation of B cells requires binding of antigen to the B-cell receptor and a survival signal from ligand-bound CD40, signals that are provided by the EBV LMP1 and LMP2A latency proteins. Recently, Toll-like receptor (TLR) signaling has been reported to provide a third B-cell activation stimulus. The interaction between the EBV and TLR pathways was therefore investigated. Both UV-inactivated and untreated EBV upregulated the expression of TLR7 and downregulated the expression of TLR9 in naive B cells. UV-inactivated virus transiently stimulated naive B-cell proliferation in the presence of the TLR7 ligand R837, while addition of the TLR7 antagonist IRS 661 impaired cell growth induced by untreated EBV. Interferon regulatory factor 5 (IRF-5) is a downstream mediator of TLR7 signaling. IRF-5 was induced following EBV infection, and IRF-5 was expressed in B-cell lines with type III latency. Expression of IRF-5 in this setting is surprising since IRF-5 has tumor suppressor and antiviral properties. B-cell proliferation assays provided evidence that EBV modulates TLR7 signaling responses. Examination of IRF-5 transcripts identified a novel splice variant, V12, that was induced by EBV infection, was constitutively nuclear, and acted as a dominant negative form in IRF-5 reporter assays. IRF-4 negatively regulates IRF-5 activation, and IRF-4 was also present in type III latently infected cells. EBV therefore initially uses TLR7 signaling to enhance B-cell proliferation and subsequently modifies the pathway to regulate IRF-5 activity.
爱泼斯坦-巴尔病毒（EBV）感染原代B细胞会导致B细胞活化和增殖。B细胞的活化需要抗原与B细胞受体结合以及来自配体结合型CD40的存活信号，而这些信号由EBV潜伏蛋白LMP1和LMP2A提供。最近，有报道称Toll样受体（TLR）信号传导可提供第三种B细胞活化刺激。因此，对EBV与TLR途径之间的相互作用进行了研究。紫外线灭活的EBV和未处理的EBV均可上调幼稚B细胞中TLR7的表达，并下调TLR9的表达。紫外线灭活的病毒在TLR7配体R837存在的情况下可短暂刺激幼稚B细胞增殖，而添加TLR7拮抗剂IRS 661会损害未处理的EBV诱导的细胞生长。干扰素调节因子5（IRF-5）是TLR7信号传导的下游介质。EBV感染后可诱导IRF-5表达，并且IRF-5在具有III型潜伏的B细胞系中表达。在这种情况下IRF-5的表达令人惊讶，因为IRF-5具有肿瘤抑制和抗病毒特性。B细胞增殖试验提供了证据表明EBV可调节TLR7信号反应。对IRF-5转录本的检查发现了一种新的剪接变体V12，它由EBV感染诱导，组成性定位于细胞核，并在IRF-5报告基因试验中作为显性负性形式发挥作用。IRF-4负调节IRF-5的活化，并且IRF-4也存在于III型潜伏感染的细胞中。因此，EBV最初利用TLR7信号传导来增强B细胞增殖，随后改变该途径以调节IRF-5活性。
