Li Lihong, Li Zhuoran, Li Xin, Wang Erlin, Lang Fengchao, Xia Yujie, Fraser Nigel W, Gao Feng, Zhou Jumin
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, China.
Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China.
J Neurovirol. 2016 Jun;22(3):293-306. doi: 10.1007/s13365-015-0393-4. Epub 2015 Oct 26.
Herpes Simplex Virus type I (HSV-1) latently infects peripheral nervous system (PNS) sensory neurons, and its reactivation leads to recurring cold sores. The reactivated HSV-1 can travel retrograde from the PNS into the central nervous system (CNS) and is known to be causative of Herpes Simplex viral encephalitis. HSV-1 infection in the PNS is well documented, but little is known on the fate of HSV-1 once it enters the CNS. In the murine model, HSV-1 genome persists in the CNS once infected through an ocular route. To gain more details of HSV-1 infection in the CNS, we characterized HSV-1 infection of the tree shrew (Tupaia belangeri chinensis) brain following ocular inoculation. Here, we report that HSV-1 enters the tree shrew brain following ocular inoculation and HSV-1 transcripts, ICP0, ICP4, and LAT can be detected at 5 days post-infection (p.i.), peaking at 10 days p.i. After 2 weeks, ICP4 and ICP0 transcripts are reduced to a basal level, but the LAT intron region continues to be expressed. Live virus could be recovered from the olfactory bulb and brain stem tissue. Viral proteins could be detected using anti-HSV-1 antibodies and anti-ICP4 antibody, during the acute stage but not beyond. In situ hybridization could detect LAT during acute infection in most brain regions and in olfactory bulb and brain stem tissue well beyond the acute stage. Using a homogenate from these tissues' post-acute infection, we did not recover live HSV-1 virus, supporting a latent infection, but using a modified explant cocultivation technique, we were able to recover reactivated virus from these tissues, suggesting that the HSV-1 virus latently infects the tree shrew CNS. Compared to mouse, the CNS acute infection of the tree shrew is delayed and the olfactory bulb contains most latent virus. During the acute stage, a portion of the infected tree shrews exhibit symptoms similar to human viral encephalitis. These findings, together with the fact that tree shrews are closely related to primates, provided a valuable alternative model to study HSV-1 infection and pathogenesis in the CNS.
I型单纯疱疹病毒（HSV-1）潜伏感染外周神经系统（PNS）的感觉神经元，其重新激活会导致复发性唇疱疹。重新激活的HSV-1可从PNS逆行进入中枢神经系统（CNS），已知可引发单纯疱疹病毒性脑炎。HSV-1在PNS中的感染已有充分记录，但对于HSV-1一旦进入CNS后的命运却知之甚少。在小鼠模型中，HSV-1基因组一旦通过眼部途径感染就会在CNS中持续存在。为了更详细地了解HSV-1在CNS中的感染情况，我们对经眼部接种后树鼩（Tupaia belangeri chinensis）大脑中的HSV-1感染进行了表征。在此，我们报告HSV-1经眼部接种后进入树鼩大脑，并且在感染后5天（p.i.）可检测到HSV-1转录本、ICP0、ICP4和LAT，在感染后10天达到峰值。2周后，ICP4和ICP0转录本降至基础水平，但LAT内含子区域继续表达。活病毒可从嗅球和脑干组织中回收。在急性期可使用抗HSV-1抗体和抗ICP4抗体检测到病毒蛋白，但之后则检测不到。原位杂交可在大多数脑区的急性感染期间以及在急性期过后很长时间在嗅球和脑干组织中检测到LAT。使用这些组织急性感染后的匀浆，我们未回收活的HSV-1病毒，支持潜伏感染，但使用改良的外植体共培养技术，我们能够从这些组织中回收重新激活的病毒，表明HSV-1病毒潜伏感染树鼩CNS。与小鼠相比，树鼩的CNS急性感染延迟，且嗅球中含有最多的潜伏病毒。在急性期，一部分受感染的树鼩表现出与人类病毒性脑炎相似的症状。这些发现，连同树鼩与灵长类密切相关这一事实，为研究HSV-1在CNS中的感染和发病机制提供了一个有价值的替代模型。
