MOLECULAR PATHOGENESIS OF VARICELLA ZOSTER VIRUS INFECTION

水痘带状疱疹病毒感染的分子发病机制

• 批准号: 8358032
• 负责人: VICKI L TRAINA-DORGE
• 金额: $ 3.72万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358032
• 关键词: Affect; Autopsy; Biopsy; Cercopithecus pygerythrus; Cessation of life; Chickenpox; Cytoplasm; Detection; Dose; Exanthema; Frequencies; Funding; Ganglia; Gene Expression; Genetic Transcription; Grant; Herpes zoster disease; Herpesvirus Type 3; Human; Immunosuppression; Immunosuppressive Agents; Infection; Lung; Macaca; Molecular; Monkeys; National Center for Research Resources; Neurons; Open Reading Frames; Pathogenesis; Primates; Principal Investigator; Process; Proteins; RNA; Research; Research Infrastructure; Resources; Skin; Source; Stress; Tacrolimus; Tissues; United States National Institutes of Health; Viral Antigens; Virus; Virus Diseases; Virus Latency; cost; immunosuppressed; irradiation; social; viral DNA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Simian varicella virus (SVV) infection of primates resembles human varicella-zoster virus (VZV) infection. After primary infection, SVV becomes latent in ganglia and reactivates after immunosuppression or social and environmental stress. Herein, natural SVV infection was established in 5 cynomolgus macaques (cynos) and 10 African green (AG) monkeys. Four cynos were treated with the immunosuppressant tacrolimus (80 to 300 ¿g/kg/day) for 4 months and 1 was untreated (group 1). Four AG monkeys were exposed to a single dose (200 cGy) of x-irradiation (group 2), and 4 other AG monkeys were irradiated and treated with tacrolimus for 4 months (group 3); the remaining 2 AG monkeys were untreated. Zoster rash developed 1 to 2 weeks after tacrolimus treatment in 3 of 4 monkeys in group 1, 6 weeks after irradiation in 1 of 4 monkeys in group 2, and 1 to 2 weeks after irradiation in all 4 monkeys in group 3. All monkeys were euthanized 1 to 4 months after immunosuppression. SVV antigens were detected immunohistochemically in skin biopsies as well as in lungs of most monkeys. Low copy number SVV DNA was detected in ganglia from all three groups of monkeys, including controls. RNA specific for SVV ORFs 61, 63, and 9 was detected in ganglia from one immunosuppressed monkey in group 1. SVV antigens were detected in multiple ganglia from all immunosuppressed monkeys in every group, but not in controls. These results indicate that tacrolimus treatment produced reactivation in more monkeys than irradiation and tacrolimus and irradiation increased the frequency of SVV reactivation as compared to either treatment alone. Studies of varicella-zoster virus gene expression during latency require the acquisition of human ganglia at autopsy. Concerns have been raised that the virus might reactivate immediately after death. Because features of varicella-zoster virus latency are similar in primate and human ganglia, we examined virus gene expression in tissues either processed immediately or kept at 4¿C for 30 h before necropsy of two monkeys inoculated with SVV and euthanized 117 days later. Virus transcription and the detection of open reading frame (ORF) 63 protein in the cytoplasm of neurons were comparable. Thus, a 30-h delay after death did not affect varicella-zoster virus expression in latently infected ganglia.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 灵长类动物的猴水痘病毒（SVV）感染与人类水痘带状疱疹病毒（VZV）感染相似。初次感染后，SVV潜伏在神经节中，并在免疫抑制或社会和环境压力后重新激活。在此，在5只食蟹猴（cynomolgus macaques，cynos）和10只非洲绿色（African green，AG）猴中建立自然SVV感染。4只食蟹猴接受免疫抑制剂他克莫司（80至300 μ g/kg/天）治疗4个月，1只未接受治疗（第1组）。4只AG猴暴露于单次剂量（200 cGy）的X射线照射（第2组），另外4只AG猴接受照射并接受他克莫司治疗4个月（第3组）;其余2只AG猴未接受治疗。第1组中3/4只猴在他克莫司治疗后1 - 2周、第2组中1/4只猴在照射后6周和第3组中所有4只猴在照射后1 - 2周发生带状疱疹。免疫抑制后1至4个月对所有猴实施安乐死。 SVV抗原检测化学皮肤活检，以及在大多数猴子的肺。在所有三组猴（包括对照组）的神经节中均检测到低拷贝数SVV DNA。在第1组1只免疫抑制猴的神经节中检测到SVV ORF 61、63和9的特异性RNA。SVV抗原在各组免疫抑制猴的多个神经节中检测到，但在对照组中未检测到。这些结果表明，他克莫司治疗比辐射在更多的猴子中产生再激活，并且与单独治疗相比，他克莫司和辐射增加了SVV再激活的频率。 水痘带状疱疹病毒潜伏期基因表达的研究需要在尸检时获得人类神经节。人们担心，这种病毒可能会在人死后立即重新激活。由于水痘-带状疱疹病毒潜伏期的特征在灵长类动物和人类神经节中相似，我们检测了组织中病毒基因的表达，这些组织要么立即处理，要么在4 ℃下保存30小时，然后对接种SVV并在117天后安乐死的两只猴子进行尸检。病毒的转录和开放阅读框（ORF）63蛋白在神经元胞质中的检测具有可比性。因此，死亡后30小时的延迟并不影响水痘带状疱疹病毒在潜伏感染的神经节中的表达。