Patchwork pattern of transcriptional reactivation in the lungs indicates sequential checkpoints in the transition from murine cytomegalovirus latency to recurrence
Patchwork pattern of transcriptional reactivation in the lungs indicates sequential checkpoints in the transition from murine cytomegalovirus latency to recurrence
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DOI：
10.1128/jvi.73.10.8612-8622.1999
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发表时间：
1999-10-01
影响因子：
5.4
通讯作者：
Reddehase, MJ
中科院分区：
文献类型：
--
作者：
Kurz, SK;Reddehase, MJ
肺是鼠巨细胞病毒（mCMV）潜伏期的重要器官部位。我们已经证明，驱动ie 1-ie 3转录单位转录的主要立即早期启动子（MIEP）的活性并不必然启动生产循环（S。K. Kurz，M.拉普，H.- P. Steffens，N. K; A. Grzimek，S. Schmalz和M. Reddehase，J，Virol. 73：482-494，1999）。因此，尽管由MIEP增强子控制的MIEP活性无疑是复发的第一个条件，但转录因子对增强子的调节不是控制潜伏期的唯一机制。具体而言，在潜伏期，局灶性和随机MIEP活动在肺组织中被发现选择性地产生IE 1的成绩单，而反式激活因子指定IE 3成绩单丢失。这表明对mCMV潜伏期的控制在IE 1-IE 3前体mRNA共转录加工中有效。在此，我们使用该模型研究了血液消融、遗传毒性治疗后单个肺组织块中再激活和复发的动力学。值得注意的是，激活被触发，但肺中转录活性灶的数量并没有随着时间的推移而增加。这一结果与撤销免疫控制后自发再激活累积的模型不一致。相反，数据支持的想法，重新激活是一个诱发事件。在一些片段中，病灶再活化产生IE 3转录本，但不产生gB转录本，而其他片段包含已经进行gB转录的病灶，并且只有少数病灶实际上达到病毒复发的状态。这一发现表明，在从mCMV潜伏期到复发的过渡中存在几个顺序排列的控制点。
The lungs are a significant organ site of murine cytomegalovirus (mCMV) latency. We have shown that activity of the major immediate-early promoter (MIEP), which drives the transcription from the ie1-ie3 transcription unit, does not inevitably initiate the productive cycle (S. K. Kurz, M. Rapp, H.-P. Steffens, N. K; A. Grzimek, S. Schmalz, and M. J. Reddehase, J, Virol. 73:482-494, 1999). Thus, even though MIEP activity governed by the MIEP-enhancer is unquestionably the first condition for recurrence, regulation of the enhancer by transcription factors is not the only mechanism controlling latency. Specifically, during latency, focal and stochastic MIEP activity in lung tissue was found to selectively generate IE1 transcripts, while transactivator-specifying IE3 transcripts were missing. This suggested a control of mCMV latency that is effectual at IE1-IE3 precursor mRNA cotranscriptional processing. Here we have used this model for studying the kinetics of reactivation and recurrence in individual lung tissue pieces after hematoablative, genotoxic treatment. Notably, reactivation was triggered, but the number of transcriptionally active foci in the lungs did not increase over time. This result is not compatible with a model of spontaneous reactivations accumulating after withdrawal of immune control. Instead, the data support the idea that reactivation is an induced event. In some pieces, focal reactivation generated IE3 transcripts but not gB transcripts, while other pieces contained foci that had proceeded to gB transcription, and only a few foci actually reached the state of virus recurrence. This finding indicates the existence of several sequentially ordered control points in the transition from mCMV latency to recurrence.