IMMUNITY TO HSV1 INFECTION IN THE NERVOUS SYSTEM

HSV-1感染可在首次感染部位产生复发的病毒损害，并有能力导致严重疾病。疱疹间质角膜炎(HSK)是由HSV-1感染引起的一种此类疾病，是美国境内导致人类角膜失明的主要原因。这种疾病被认为是由免疫介导的，几名研究人员已经开始剖析其中的潜在机制。虽然许多这些研究都集中在免疫机制上，如细胞因子的存在或不存在对疾病进展的影响，但很少有人确定这些免疫因素对病毒基因调控或感觉神经元内复制的影响，而感觉神经元是已知的潜伏的HSV-1。控制HSV-1潜伏状态的机制仍然不清楚。利用本实验室开发的体外神经元模型，可以直接检查神经元，并有助于确定哪些免疫因素有助于维持或重新激活潜伏感染HSV-1的神经元。免疫调节和HSV-1感染对神经元基因调控的影响也可以用这个系统来检测。HSK小鼠模型将用于体内研究HSV-1感染。免疫缺陷小鼠将被用来确定在我们的研究中发现对体外神经元HSV-1潜伏期模型的维持或重新激活有影响的免疫成分是否参与体内HSV-1感染的建立、维持或重新激活。了解HSV潜伏期和重新激活所涉及的事件将可能导致免疫治疗技术的发展，这可能会潜在地改善破坏性免疫反应或增强针对HSV-1感染的保护性免疫反应。

HSV-1 infections can produce recurrent viral lesions at the site of initial infection and has the ability to cause severe disease. Herpetic stromal keratitis (HSK) is one such disease caused by HSV-1 infection and is the leading cause of corneal blindness in humans within the United States. This disease is thought to be immune-mediated and several investigators have started to dissect the potential mechanisms involved. While many of these investigations have focused on immune mechanisms such as the presence or absence of cytokines on disease progression, very little has been done to determine the effects of these immune factors on viral gene regulation or replication within the sensory neuron which is known to harbor latent HSV-1. The mechanisms that control the latent state of HSV-1 remain elusive. The utilization of an in vitro neuronal model, developed in this laboratory, allows for the direct examination of the neuron and is useful for determining which immune factors contribute to the maintenance or reactivation of HSV-1 latently infected neurons. The effects of immune modulation and HSV-1 infection on the regulation of neuronal genes can also be examined using this system. The HSK mouse model will be used to stud) HSV-1 infection in vivo. Immune deficient mice will be used to determine if immune components, which are discovered in our studies to have an effect on maintenance or reactivation in the in vitro neuronal HSV-1 latency model are involved in the establishment, maintenance or reactivation of HSV- 1 infection in vivo. Understanding the events involved in the establishment of HSV latency and reactivation will conceivably lead to the development of immunotherapeutic techniques which may potentially ameliorate damaging immune responses or enhance the protective immune responses against infection with HSV-1.