昆明动物所首次成功建立理想的单纯疱疹病毒感染模型

rojjer

单纯疱疹病毒（herpessimplexvirus,hsv）是人类最常见的病原体，世界人口中超过80%的人都感染过hsv，一旦感染则终身潜伏。在应激等情况下，潜伏的病毒会被重激活，引起口唇疱疹、角膜炎或生殖器疱疹等；部分重激活的病毒会沿着神经突触进入中枢神经系统，引起疱疹病毒性脑炎，导致不可逆的神经性损伤甚至死亡。至今还没有针对hsv潜伏感染的有效治疗手段。

目前，啮齿类是研究疱疹病毒潜伏感染的主要动物模型，但此类模型有着显著的缺点，不能很好地模拟人类疱疹病毒潜伏感染的情况。树鼩是一种小型，接近于灵长类的哺乳动物。为了进一步将树鼩发展成为研究疱疹病毒感染的有用模型，中国科学院昆明动物研究所周巨民课题组李丽红、李卓然、王二林等用hsv-1经眼部接种感染树鼩，成功建立了hsv-1潜伏感染模型并对其重激活进行了研究。

他们发现树鼩的hsv-1感染与小鼠感染存在显著差别并与人类感染有更多类似。在急性感染期，树鼩出现与人类的疱疹病毒性角膜炎相似的眼部疾病。部分感染严重的树鼩，甚至表现出与人类疱疹病毒性脑炎相似的症状。hsv-1能够在树鼩的三叉神经节建立潜伏感染；这些病毒可以被诱导激活，或自发地在泪液中释放有感染活性的病毒。有趣的是hsv-1在树鼩三叉神经节中表现出一种温和的急性感染症状，检测不到感染性的病毒，因此不会导致神经元死亡。这一点类似人类感染，因为人类感染疱疹或病毒再激活时，并不引起疱疹组织部位知觉的丧失。更重要的是，他们发现树鼩脑中潜伏的病毒可原位重激活。这一研究结果对hsv引起的病毒性脑膜炎的发病机制和干预有重要意义。

该研究的部分结果以hsv-1infectionoftreeshrewsdiffersfromthatofmiceintheseverityofacuteinfectionandviraltranscriptionintheperipheralnervoussystem为题在线发表于journalofvirology，以reactivationofhsv-1followingexplantoftreeshrewbrain为题在线发表于journalofneurovirolog。博士研究生李丽红为第一作者，研究员周巨民为通讯作者。

该研究得到了中科院百人计划、云南省高端人才项目和云南省自然科学基金重点项目的资助。（中国科学院网）

Biodog

单纯疱疹病毒（Herpes Simplex Virus, HSV）是人类最常见的病原体，世界人口中超过80%的人都感染过HSV，一旦感染则终身潜伏。在应激等情况下，潜伏的病毒会被重激活，引起口唇疱疹、角膜炎或生殖器疱疹等；部分重激活的病毒会沿着神经突触进入中枢神经系统，引起疱疹病毒性脑炎，导致不可逆的神经性损伤甚至死亡。至今还没有针对HSV潜伏感染的有效治疗手段。

目前，啮齿类是研究疱疹病毒潜伏感染的主要动物模型，但此类模型有着显著的缺点，不能很好地模拟人类疱疹病毒潜伏感染的情况。树鼩是一种小型，接近于灵长类的哺乳动物。为了进一步将树鼩发展成为研究疱疹病毒感染的有用模型，中国科学院昆明动物研究所周巨民课题组李丽红、李卓然、王二林等用HSV-1经眼部接种感染树鼩，成功建立了HSV-1潜伏感染模型并对其重激活进行了研究。

他们发现树鼩的HSV-1感染与小鼠感染存在显著差别并与人类感染有更多类似。在急性感染期，树鼩出现与人类的疱疹病毒性角膜炎相似的眼部疾病。部分感染严重的树鼩，甚至表现出与人类疱疹病毒性脑炎相似的症状。HSV-1能够在树鼩的三叉神经节建立潜伏感染；这些病毒可以被诱导激活，或自发地在泪液中释放有感染活性的病毒。有趣的是HSV-1在树鼩三叉神经节中表现出一种温和的急性感染症状，检测不到感染性的病毒，因此不会导致神经元死亡。这一点类似人类感染，因为人类感染疱疹或病毒再激活时，并不引起疱疹组织部位知觉的丧失。更重要的是，他们发现树鼩脑中潜伏的病毒可原位重激活。这一研究结果对HSV引起的病毒性脑膜炎的发病机制和干预有重要意义。

该研究的部分结果以HSV-1 infection of tree shrews differs from that of mice in the severity of acute infection and viral transcription in the peripheral nervous system 为题在线发表于Journal of Virology，以Reactivation of HSV-1 following explant of tree shrew brain 为题在线发表于Journal of Neurovirolog。博士研究生李丽红为第一作者，研究员周巨民为通讯作者。

该研究得到了中科院百人计划、云南省高端人才项目和云南省自然科学基金重点项目的资助。

http://jvi.asm.org/content/early/2015/10/22/JVI.02258-15.abstract

http://link.springer.com/article/10.1007/s13365-015-0393-4/fulltext.html

bigben446

【标题】：Herpes Simplex Virus 1 Infection of Tree Shrews Differs from That of Mice in the  Severity of Acute Infection and Viral Transcription in the Peripheral Nervous System
【作者】：Li, L.; Li, Z.; Wang, E. (...)
【来源】：J Virol, 2015, 90(2), 790-804
【摘要】：Studies of herpes simplex virus (HSV) infections of humans are limited by the use of rodent models such as mice, rabbits, and guinea pigs. Tree shrews (Tupaia belangeri chinensis) are small mammals indigenous to southwest Asia. At behavioral, anatomical, genomic, and evolutionary levels, tree shrews are much closer to primates than rodents are, and tree shrews are susceptible to HSV infection. Thus, we have studied herpes simplex virus 1 (HSV-1) infection in the  tree shrew trigeminal ganglion (TG) following ocular inoculation. In situ hybridization, PCR, and quantitative reverse transcription-PCR (qRT-PCR) analyses confirm that HSV-1 latently infects neurons of the TG. When explant cocultivation of trigeminal ganglia was performed, the virus was recovered after 5 days of cocultivation with high efficiency. Swabbing the corneas of latently infected tree shrews revealed that tree shrews shed virus spontaneously at low frequencies. However, tree shrews differ significantly from mice in the expression of key HSV-1 genes, including ICP0, ICP4, and latency-associated transcript (LAT). In acutely infected tree shrew TGs, no level of ICP4 was observed, suggesting the absence of infection or a very weak, acute infection compared to that of the mouse. Immunofluorescence staining with ICP4 monoclonal antibody, and immunohistochemistry detection by HSV-1 polyclonal antibodies, showed a lack of viral proteins in tree shrew TGs during both acute and latent phases of infection. Cultivation of supernatant from homogenized, acutely infected TGs with RS1 cells also exhibited an absence of infectious HSV-1 from tree shrew TGs. We conclude that the tree shrew has an undetectable, or a much weaker, acute infection in the TGs. Interestingly, compared to mice, tree shrew TGs express high levels of ICP0 transcript in addition to LAT during latency. However, the ICP0 transcript remained nuclear, and no ICP0 protein could be seen  during the course of mouse and tree shrew TG infections. Taken together, these observations suggest that the tree shrew TG infection differs significantly from  the existing rodent models. IMPORTANCE: Herpes simplex viruses (HSVs) establish lifelong infection in more than 80% of the human population, and their reactivation leads to oral and genital herpes. Currently, rodent models are the preferred models for latency studies. Rodents are distant from primates and may not fully represent human latency. The tree shrew is a small mammal, a prosimian  primate, indigenous to southwest Asia. In an attempt to further develop the tree  shrew as a useful model to study herpesvirus infection, we studied the establishment of latency and reactivation of HSV-1 in tree shrews following ocular inoculation. We found that the latent virus, which resides in the sensory  neurons of the trigeminal ganglion, could be stress reactivated to produce infectious virus, following explant cocultivation and that spontaneous reactivation could be detected by cell culture of tears. Interestingly, the tree  shrew model is quite different from the mouse model of HSV infection, in that the virus exhibited only a mild acute infection following inoculation with no detectable infectious virus from the sensory neurons. The mild infection may be more similar to human infection in that the sensory neurons continue to function  after herpes reactivation and the affected skin tissue does not lose sensation. Our findings suggest that the tree shrew is a viable model to study HSV latency.