MOLECULAR PATHOGENESIS OF VARICELLA ZOSTER VIRUS INFECTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 猴可感染猴水痘病毒(SVV)，其临床、病理、免疫学和病毒学特征与人类VZV感染几乎相同。同样与人类相似，感染后8-12周，病毒在背根神经节中潜伏，并有可能重新激活。我们早期的工作在非洲绿猴身上建立了一个潜伏期/重新激活模型。潜伏感染的AGM通过免疫抑制和X-射线检测，并被证明启动了SVV的重新激活。非人灵长类动物模型最初是在年度股东大会上作为自然传播模型开发的。将血清SVV阴性的猴子作为笼子暴露在接种了SVV的其他猴子身上。接种的猴子会受到感染，出现水痘，但病毒在外周循环、肺和肝脏中持续数周/数月。然而，暴露在病毒中的猴子患上了水痘，但能够迅速从血液中清除病毒，8-12周后，病毒只在神经组织中发现，而在肺或肝脏中没有发现。一项典型的研究包括8只动物：3只接种，5只暴露。 Messaoudi等人在2009年进行的一项最新研究表明，猕猴体内感染SVV会导致类似的潜伏期，而不是持续性感染。由于需要使用更多的动物来完成自然暴露，我们想要证实这些发现。在猕猴身上进行了一项小型研究，以测试另一物种在直接接种SVV后形成潜伏期的能力。2只血清阴性恒河猴气管内接种1×10E4SVV，观察病毒学和临床表现。两只动物都被感染，出现典型的水痘皮疹，循环病毒在接种后12天达到高峰。我们对动物进行了14周的跟踪，发现病毒在8周内显着清除，表明存在潜伏期。我们对这两只动物进行了尸检，目前正在评估肺、肝和神经节中的病毒水平，以最终确认潜伏期。如果它们最终得到确认，我们将改用恒河猴进行这项拨款中建议的其余研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Monkeys can be infected with simian varicella virus (SVV), with clinical, pathological, immunological and virological features virtually identical to those of VZV infection in humans. Also similar to humans, following 8-12 weeks post infection, the virus becomes latent in the dorsal root ganglia and have the potential to reactivate. Our earlier work developed a latency/reactivation model in the African green monkey. Latently-infected AGM were tested by immunosuppression and X-irradiation and were shown to initiate SVV reactivation. The nonhuman primate model was originally developed in the AGM as a natural transmission model. SVV-seronegative monkeys were exposed as cagemates to other monkeys that had been inoculated with SVV. The inoculated monkeys became infected, developed chickenpox but virus persisted for weeks/months in the peripheral circulation, lungs, and liver. The exposed monkeys, however, developed chickenpox but were able to clear virus from the bloodstream quickly and by 8-12 weeks, virus was found only in nerve tissue but not in lung or liver. A typical study consisted of 8 animals: 3 inoculated and 5 exposed. A recent study by Messaoudi et al., 2009, proposed that SVV infection in rhesus macaque results in a similar latency rather than persistent infection. Due to the needed use of increased numbers of animals to accomplish natural exposure, we wanted to confirm these findings. A small study was conducted in rhesus macaque to test the ability of another species to develop latency following direct inoculation of SVV. Two seronegative rhesus macaques were intratracheal inoculated with 1 x 10e4 SVV and followed for virolgical and clinical findings. Both animals were infected, developed typical chickenpox rash, and circulating virus peaking at d12 post inoculation. We followed the animals for 14 weeks and demonstrated significant clearance of virus by 8 weeks suggesting latency. We conducted necropsy of both animals and are currently assessing levels of virus in lung, liver and ganglia for final confirmation of latency. If they are finally confirmed, we will switch to the rhesus for use in conducting the remaining studies proposed in this grant.