Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo.
Deletion of the CTRL2 Insulator in HSV-1 Results in the Decreased Expression of Genes Involved in Axonal Transport and Attenuates Reactivation In Vivo.
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DOI：
10.3390/v14050909
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发表时间：
2022-04-27
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影响因子：
--
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单纯疱疹病毒1型（HSV - 1）是一种人类病原体，会在宿主体内形成终身感染。HSV - 1通过逆向轴突运输被转运至外周神经系统的感觉神经元，在那里潜伏的病毒基因组可以重新激活。重新激活产生的病毒通过顺向轴突运输到达外周，并可引发临床疾病。CCCTC结合因子（CTCF）绝缘子位于HSV - 1的潜伏期相关转录本（LAT）和立即早期（IE）区域两侧，在潜伏期通过多种功能（包括增强子阻断或屏障绝缘子功能）维持转录结构域的完整性。重要的是，在重新激活过程中，CTCF蛋白会从HSV - 1基因组上脱离，尤其是从CTRL2绝缘子上脱离。CTRL2是LAT 5′外显子区域下游的一个功能性绝缘子，因此这些结果表明，这种绝缘子的破坏可能是HSV - 1有效重新激活所必需的。为了进一步探究这一点，我们在HSV - 1感染的兔眼部模型中使用了一种缺失CTRL2绝缘子（ΔCTRL2）的重组病毒并诱导其重新激活。我们发现，在缺乏CTRL2绝缘子的情况下，HSV - 1在兔体内建立了同等程度的潜伏感染，但这些兔子无法有效地从潜伏期重新激活。此外，我们发现基因Us9的表达显著降低，Us9编码一种II型膜蛋白，已被证明是神经元顺向运输所必需的。综上所述，这些结果表明，CTRL2绝缘子的功能与重新激活神经元中Us9的激活，通过对一个负责HSV - 1向周边轴突运输的基因的调控而内在地联系在一起。
HSV-1 is a human pathogen that establishes a lifelong infection in the host. HSV-1 is transported by retrograde axonal transport to sensory neurons in the peripheral nervous system where latent viral genomes can reactivate. The resulting virus travels via anterograde axonal transport to the periphery and can cause clinical disease. CTCF insulators flank the LAT and IE regions of HSV-1 and during latency and maintain the integrity of transcriptional domains through a myriad of functions, including enhancer-blocking or barrier-insulator functions. Importantly, during reactivation, CTCF protein is evicted from the HSV-1 genome, especially from the CTRL2 insulator. CTRL2 is a functional insulator downstream of the 5′exon region of the LAT, so these results suggest that the disruption of this insulator may be required for efficient HSV-1 reactivation. To further explore this, we used a recombinant virus containing a deletion of the CTRL2 insulator (ΔCTRL2) in a rabbit ocular model of HSV-1 infection and induced reactivation. We show that, in the absence of the CTRL2 insulator, HSV-1 established an equivalent latent infection in rabbits, but those rabbits failed to efficiently reactivate from latency. Furthermore, we found a significant decrease in the expression of the gene Us9-, a gene that codes for a type II membrane protein that has been shown to be required for anterograde transport in neurons. Taken together, these results suggest that the functions of the CTRL2 insulator and Us9 activation in reactivating neurons are intrinsically linked through the regulation of a gene responsible for the axonal transport of HSV-1 to the periphery.
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