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OCULAR INFECTION WITH THE HERPES VIRUSES

疱疹病毒引起的眼部感染

基本信息

批准号：
6605728
负责人：
TODD P. MARGOLIS
金额：
$ 33.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-12-01 至 2006-06-30
项目状态：
已结题

项目摘要

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。对于复发性HSV疾病问题的解决方案的达成无疑将取决于对调节HSV潜伏感染的分子机制的更好理解。这项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，胶质细胞衍生的生长因子和artemin，有效的神经营养因子，触发细胞内信号通路的重要神经元的生存，将检查其可能的作用，促进建立HSV潜伏感染。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立即早期（IE）调节基因ICP0、ICP 4和ICP 27的表达的能力。两个群体的神经节神经元HSV感染的结果非常不同的基因表达谱将进行研究，以确定宿主基因的差异表达，并可能发挥作用，建立潜伏感染。最后，将筛选神经元cDNA表达文库中影响关键病毒调控基因表达的宿主细胞基因产物。然后测试这些基因产物在瞬时测定中抑制HSV IE启动子活性的能力和体外HSV生产性感染。总之，这些研究将开始阐明神经元在HSV感染后存活并成为导致复发性疾病的潜伏病毒储库的机制。