OCULAR INFECTION WITH THE HERPES VIRUSES

疱疹病毒引起的眼部感染

• 批准号: 6384358
• 负责人: TODD P. MARGOLIS
• 金额: $ 37.61万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6384358
• 关键词: biomarker; ganglions; gene expression; genetic transcription; genetically modified animals; growth factor receptors; herpes simplex virus 1; host organism interaction; immunofluorescence technique; in situ hybridization; interferon gamma; laboratory mouse; latent virus infection; nervous system infection; neurons; neurotrophic factors; neurotropic virus; northern blottings; ocular herpes; phenotype; regulatory gene; transcription factor; trigeminal nerve; virus genetics; virus infection mechanism; virus protein

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.

单纯疱疹病毒（HSV）的复发性感染可能影响到世界上三分之一的人口。此外，在发达国家，由HSV引起的复发性角膜疾病是感染性角膜失明的主要原因。理解由HSV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，并且复发性疾病是由于病毒从这种潜伏状态重新激活所致。对于复发性HSV疾病的解决方案无疑将取决于对调节HSV潜伏感染的分子机制的更好理解。本研究的总体目标是确定在建立单纯疱疹病毒（HSV）潜伏感染中起作用的神经元信号通路和转录因子。神经生长因子、神经胶质细胞源性生长因子和青蒿素是触发细胞内信号通路的强效神经营养因子，对神经元存活具有重要意义，我们将研究它们在促进HSV潜伏感染建立中的可能作用。转基因小鼠将用于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HSV即时早期（IE）调控基因ICPO， ICP4和ICP27表达的能力。我们将研究两种具有不同HSV感染结果的神经节神经元的基因表达谱，以确定差异表达的宿主基因，并可能在潜伏感染的建立中发挥作用。最后，将筛选影响关键病毒调控基因表达的宿主细胞基因产物的神经元cDNA表达文库。然后，这些基因产物将在短暂试验和体外HSV产生性感染中测试其抑制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如何在HSV感染中存活并成为负责复发性疾病的潜伏病毒储存库的机制。