OCULAR INFECTION WITH THE HERPES VIRUSES

反复感染单纯疱疹病毒(HSV)可能影响多达三分之一的世界人口。此外，在发达国家，单纯疱疹病毒引起的复发性角膜疾病是感染性角膜失明的主要原因。理解单纯疱疹病毒引起的疾病的病理生理学的一个重要概念是，病毒在神经元中建立潜伏感染，反复疾病是由于病毒从这种潜伏状态重新激活。对于复发的单纯疱疹病毒病的解决方案无疑将取决于对控制单纯疱疹病毒潜伏感染的分子机制的更好理解。这项拟议研究的总体目标是确定在单纯疱疹病毒(HSV)潜伏感染的建立中发挥作用的神经元信号通路和转录因子。神经生长因子、胶质细胞衍生生长因子和青蒿素，这些强有力的神经营养因子，触发细胞内对神经元生存至关重要的信号通路，将被研究它们在促进HSV潜伏感染建立方面的可能作用。转基因小鼠将被用来确定潜伏感染的建立是否部分归因于宿主神经元调节关键的HSV即刻早期(IE)基因ICPO、ICP4和ICP27的表达的能力。我们将研究HSV感染结局截然不同的两类神经节细胞的基因表达谱，以确定差异表达并可能在建立潜伏感染中发挥作用的宿主基因。最后，将从神经细胞表达文库中筛选出影响关键病毒调控基因表达的宿主细胞基因产物。这些基因产物随后将在瞬时检测和体外HSV生产性感染中测试它们抑制HSV IE启动子活性的能力。综上所述，这些研究将开始阐明神经元在HSV感染后存活下来成为潜伏病毒储存库的机制，这些病毒是导致复发疾病的原因。

Recurrent infection with herpes simplex virus (HSV) may affect up to one-third of the world's population. In addition, recurrent corneal disease due to HSV is the leading cause of infectious corneal blindness in developed countries. An important concept in understanding the pathophysiology of disease due to HSV is that the virus establishes a latent infection in neurons, and that recurrent disease is due to reactivation of the virus from this latent state. Arriving at a solution for the problem of recurrent HSV disease will undoubtedly depend on an improved understanding of the molecular mechanisms that regulate latent infection with HSV. The overall goal of the proposed research is to identify neuronal signaling pathways and transcription factors that play a role in the establishment of herpes simplex virus (HSV) latent infection. Nerve growth factor, glial-cell-derived growth factor and artemin, potent neurotrophic factors that trigger intracellular signaling pathways important for neuronal survival, will be examined for their possible roles in promoting the establishment of HSV latent infection. Transgenic mice will be used to determine whether establishment of latent infection is due, in part, to the host neuron's ability to modulate expression of the key HSV immediate early (IE) regulatory genes, ICPO, ICP4 and ICP27. The gene expression profiles of two populations of ganglionic neurons with very different outcomes of HSV infection will be studied in order to identify host genes that are differentially expressed and may play a role in the establishment of latent infection. Finally, a neuronal cDNA expression library will be screened for host cell gene products that influence expression of key viral regulatory genes. These gene products will then be tested for their ability to repress HSV IE promoter activity in transient assays and HSV productive infection in vitro. Taken together, these studies will begin to elucidate mechanisms by which neurons survive HSV infection to become reservoirs of latent virus responsible for recurrent disease.