Wharton S B, Meyers N L, Nash A A
Department of Pathology, Cambridge University, UK.
Neuropathol Appl Neurobiol. 1995 Jun;21(3):228-37. doi: 10.1111/j.1365-2990.1995.tb01054.x.
Host factors determining the outcome of herpes simplex virus type 1 (HSV-1) infection within neurons are poorly understood. This paper aims to identify regional differences in the behaviour of HSV-1 within the nervous system as an approach to investigating the role of the host environment in determining the outcome of infection. We describe a mouse model of HSV infection focused on motor neurons of the spinal cord, resulting from intramuscular injection (i.m.) and compare this with the behaviour of virus within sensory neurons following scarification of virus on to skin. Viral antigen was detectable immunohistochemically by 2 days in both models and disappeared by 9-11 days. The time course of acute infection was reflected in the i.m. group by quantitative plaque assay for virus. Inflammation and cell destruction occurred in both models, but clinical features and histological destruction were greater in the group infected via the intramuscular route. In the sensory ganglia, a latent state from which virus could be reactivated by explanation, was established with LATS expression detectable in many neurons at 35 days post-infection (p.i.), but not in non-neuronal cells. Expression of latency associated transcript (LATS) was detected in motor neutrons in spinal cords at 35 days p.i. providing evidence for establishment of a LATS-positive latent state at this site, and continued to be detectable up to 6 months post-infection. In addition, LATS was detected in white matter at late times, suggesting a non-neuronal site of latency. In contrast to the behaviour in sensory ganglia, induced reactivation from spinal cords, by explanation and nerve section, was a very rare event. We have shown that a LATS-positive latent state can be established within motor neurons of the CNS, but that there are regional differences in the biology and outcome of infection between the CNS and peripheral nervous system. We propose that this may be a useful model to study reproducibly, the behaviour of HSV-1 in a CNS environment and, by comparison with sensory ganglion infection, to explore host factors which may underlie these regional differences. The relevance of this model for using HSV-1 as a therapeutic vector for motor neurons is also discussed.
目前对决定单纯疱疹病毒1型（HSV-1）在神经元内感染结果的宿主因素了解甚少。本文旨在确定HSV-1在神经系统内行为的区域差异，以此作为研究宿主环境在决定感染结果中作用的一种方法。我们描述了一种HSV感染的小鼠模型，该模型聚焦于脊髓运动神经元，通过肌肉注射（i.m.）建立，并将其与病毒接种于皮肤后在感觉神经元内的病毒行为进行比较。在两种模型中，均可在2天通过免疫组织化学检测到病毒抗原，且在9-11天时消失。急性感染的时间进程在i.m.组通过病毒定量空斑试验得以体现。两种模型均出现炎症和细胞破坏，但经肌肉途径感染的组临床特征和组织学破坏更严重。在感觉神经节中，建立了一种潜伏状态，通过激发可使病毒重新激活，在感染后35天（p.i.）可在许多神经元中检测到潜伏相关转录物（LATS）表达，但在非神经元细胞中未检测到。在感染后35天，在脊髓运动神经元中检测到LATS表达，为该部位建立LATS阳性潜伏状态提供了证据，并且在感染后6个月仍可检测到。此外，在后期白质中也检测到LATS，提示存在非神经元潜伏部位。与感觉神经节中的行为不同，通过激发和神经切断从脊髓诱导重新激活是非常罕见的事件。我们已经表明，可在中枢神经系统的运动神经元内建立LATS阳性潜伏状态，但中枢神经系统和外周神经系统在感染生物学和结果方面存在区域差异。我们认为，这可能是一个有用的模型，可用于可重复地研究HSV-1在中枢神经系统环境中的行为，并通过与感觉神经节感染进行比较，探索可能是这些区域差异基础的宿主因素。还讨论了该模型对于将HSV-1用作运动神经元治疗载体的相关性。
