Neuronal Subtype Determines Herpes Simplex Virus 1 Latency-Associated-Transcript Promoter Activity during Latency
Neuronal Subtype Determines Herpes Simplex Virus 1 Latency-Associated-Transcript Promoter Activity during Latency
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DOI：
10.1128/jvi.00430-18
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发表时间：
2018-07-01
影响因子：
5.4
通讯作者：
Leiba, David A.
中科院分区：
文献类型：
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作者：
Cabrera, Jorge Ruben;Charron, Audra J.;Leiba, David A.
单纯疱疹病毒（HSV）在神经元中的潜伏期仍然知之甚少，而且感觉神经系统的异质性使机制研究变得复杂。在这项研究中，我们使用微流体装置中原代培养的成年三叉神经节 (TG) 小鼠神经元和体内模型来检查参与 HSV 潜伏期的感觉神经元的亚型。 HSV感染的神经丝重阳性（NefH（+））神经元比感染的神经丝重阴性（NefH-）神经元更有可能表达潜伏期相关转录本（LAT）。 LAT启动子的这种差异表达与HSV-1早期感染的差异相关，表现为远端轴突感染后HSV颗粒到达细胞体的效率差异。在体内，我们进一步鉴定了共表达降钙素基因相关肽α的NefH（+）神经元的特定子集（NefH（+）CGRP（+）神经元）作为HSV-1感染后LAT启动子活性最高的感觉神经元亚群。最后，早期再激活测定显示 HSV-1 在 NefH(+) CGRP(+) 神经元中重新激活，尽管其他感觉神经元亚群也参与其中。总之，这些结果表明表达神经丝的感觉神经元表现出增强的 LAT 启动子活性。我们推测，感染早期 HSV-1 入侵效率的降低可能会促进 NefH(+) 神经元潜伏期的有效建立，因为在病毒到达神经元细胞体之前就启动了抗病毒状态。虽然 HSV-1 感染神经元的结果是由体内多种因素决定的，但神经元亚型可能在调节潜伏感染的建立中发挥不同的作用。重要性 HSV-1 的两个关键特性使其成为一种成功的病原体。首先，它感染具有免疫特权的神经元。其次，它在这些神经元中建立了潜伏期。这些特性共同使得单纯疱疹病毒能够在其宿主的一生中持续存在。神经元是多样化且高度组织化的细胞，具有特定的解剖学、生理学和分子特征。先前的研究表明，HSV-1 建立潜伏期的情况在所有类型的神经元中并不相同。我们的结果表明，HSV 感染的动力学和潜伏期相关基因的表达水平在某些类型的神经元中有所不同。因此，HSV 感染的神经元亚型是感染结果和潜伏期的关键决定因素。
Herpes simplex virus (HSV) latency in neurons remains poorly understood, and the heterogeneity of the sensory nervous system complicates mechanistic studies. In this study, we used primary culture of adult trigeminal ganglion (TG) mouse neurons in microfluidic devices and an in vivo model to examine the sub-types of sensory neurons involved in HSV latency. HSV-infected neurofilament heavypositive (NefH(+)) neurons were more likely to express latency-associated transcripts (LATs) than infected neurofilament heavy-negative (NefH-) neurons. This differential expression of the LAT promoter correlated with differences in HSV-1 early infection that manifested as differences in the efficiency with which HSV particles reached the cell body following infection at the distal axon. In vivo, we further identified a specific subset of NefH(+) neurons which coexpressed calcitonin gene-related peptide alpha (NefH(+) CGRP(+) neurons) as the sensory neuron subpopulation with the highest LAT promoter activity following HSV-1 infection. Finally, an early-phase reactivation assay showed HSV-1 reactivating in NefH(+) CGRP(+) neurons, although other sensory neuron subpopulations were also involved. Together, these results show that sensory neurons expressing neurofilaments exhibit enhanced LAT promoter activity. We hypothesize that the reduced efficiency of HSV-1 invasion at an early phase of infection may promote efficient establishment of latency in NefH(+) neurons due to initiation of the antiviral state preceding arrival of the virus at the neuronal cell body. While the outcome of HSV-1 infection of neurons is determined by a broad variety of factors in vivo, neuronal subtypes are likely to play differential roles in modulating the establishment of latent infection.IMPORTANCE Two pivotal properties of HSV-1 make it a successful pathogen. First, it infects neurons, which are immune privileged. Second, it establishes latency in these neurons. Together, these properties allow HSV to persist for the lifetime of its host. Neurons are diverse and highly organized cells, with specific anatomical, physiological, and molecular characteristics. Previous work has shown that establishment of latency by HSV-1 does not occur equally in all types of neurons. Our results show that the kinetics of HSV infection and the levels of latency-related gene expression differ in certain types of neurons. The neuronal subtype infected by HSV is therefore a critical determinant of the outcome of infection and latency.