Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes
Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes
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DOI：
10.1128/jvi.01762-13
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发表时间：
2013-11-01
影响因子：
5.4
通讯作者：
Bhaduri-McIntosha, Sumita
中科院分区：
文献类型：
--
作者：
Hill, Erik R.;Koganti, Siva;Bhaduri-McIntosha, Sumita
EB病毒（EBV）的裂解激活是其生命周期和大多数EBV相关疾病的核心。然而，不是每个EBV感染的B细胞都对裂解活化敏感。这种对裂解活化的均匀易感性的缺乏也直接影响了EBV癌症的病毒溶瘤疗法的成功，但对裂解诱导信号的易感性的决定因素还没有很好地理解。为了确定宿主因素是否影响对EB病毒裂解激活的易感性，我们开发了一种将裂解细胞与难治性细胞分开的技术，并报告EB病毒裂解激活优先发生在信号转导子和转录激活子3（STAT 3）水平较低的细胞中。使用这种工具来检测单细胞，我们现在将STAT 3与溶解性与难治性状态之间的相关性扩展到原发性EBV感染患者中EBV感染的循环B细胞，从而使我们研究STAT 3是否控制对EBV溶解性激活的易感性。在EBV阳性B淋巴瘤和淋巴母细胞样细胞的功能丧失和功能获得研究中，我们发现功能性STAT3的水平调节对EBV裂解活化的易感性。这促使我们确定了一组可能受STAT3调控以限制EBV裂解激活的候选细胞基因。从这个池中，我们证实了一组已知参与转录抑制的基因在难治性细胞中的转录水平增加。总之，我们的研究结果将STAT3置于EBV潜伏期和裂解激活之间的关键十字路口，这是EBV淋巴瘤发生的基础过程。
Lytic activation of Epstein-Barr virus (EBV) is central to its life cycle and to most EBV-related diseases. However, not every EBV-infected B cell is susceptible to lytic activation. This lack of uniform susceptibility to lytic activation also directly impacts the success of viral oncolytic therapy for EBV cancers, yet determinants of susceptibility to lytic induction signals are not well understood. To determine if host factors influence susceptibility to EBV lytic activation, we developed a technique to separate lytic from refractory cells and reported that EBV lytic activation occurs preferentially in cells with lower levels of signal transducer and activator of transcription 3 (STAT3). Using this tool to detect single cells, we now extend the correlation between STAT3 and lytic versus refractory states to EBV-infected circulating B cells in patients with primary EBV infection, leading us to investigate whether STAT3 controls susceptibility to EBV lytic activation. In loss-of-function and gain-of-function studies in EBV-positive B lymphoma and lymphoblastoid cells, we found that the levels of functional STAT3 regulate susceptibility to EBV lytic activation. This prompted us to identify a pool of candidate cellular genes that might be regulated by STAT3 to limit EBV lytic activation. From this pool, we confirmed increases in transcript levels in refractory cells of a set of genes known to participate in transcription repression. Taken together, our findings place STAT3 at a critical crossroads between EBV latency and lytic activation, processes fundamental to EBV lymphomagenesis.