Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA
J Virol. 2018 Jun 13;92(13). doi: 10.1128/JVI.00430-18. Print 2018 Jul 1.
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 model to examine the subtypes of sensory neurons involved in HSV latency. HSV-infected neurofilament heavy-positive (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. , we further identified a specific subset of NefH neurons which coexpressed calcitonin gene-related peptide α (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 , neuronal subtypes are likely to play differential roles in modulating the establishment of latent infection. 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.
单纯疱疹病毒 (HSV) 在神经元中的潜伏机制仍不清楚，而感觉神经系统的异质性使得机制研究变得复杂。在这项研究中，我们使用微流控装置中的成年三叉神经节 (TG) 鼠神经元原代培养物和一种模型来研究参与 HSV 潜伏的感觉神经元亚型。与感染神经丝重链阴性 (NefH) 神经元相比，感染神经丝重链阳性 (NefH) 神经元更有可能表达潜伏相关转录本 (LAT)。这种 LAT 启动子的差异表达与 HSV-1 早期感染的差异相关，表现为感染后病毒颗粒到达细胞体的效率不同，而感染部位在远端轴突。此外，我们进一步确定了一个特定的 NefH 神经元亚群，即共同表达降钙素基因相关肽 α (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，早期再激活实验显示 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。我们假设，在感染的早期阶段，HSV-1 的入侵效率降低可能会促进 NefH 神经元中潜伏期的有效建立，因为在病毒到达神经元细胞体之前，抗病毒状态就已经开始启动。虽然神经元中 HSV-1 感染的结果取决于多种因素，但神经元亚型可能在调节潜伏感染的建立方面发挥不同的作用。HSV-1 成为成功病原体有两个关键特性。首先，它感染免疫特权的神经元。其次，它在这些神经元中建立潜伏。这两个特性使 HSV 能够在其宿主的一生中持续存在。神经元是多样且高度组织化的细胞，具有特定的解剖、生理和分子特征。先前的工作表明，HSV-1 建立潜伏并不在所有类型的神经元中都同样发生。我们的结果表明，HSV 感染的动力学和与潜伏相关的基因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和潜伏结果的关键决定因素。
