HSV INDUCED RNA DEGRADATION AND PATHOGENESIS

HSV 诱导的 RNA 降解和发病机制

• 批准号: 2888450
• 负责人: David A Leib
• 金额: $ 23.04万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2888450
• 关键词: confocal scanning microscopy; gene deletion mutation; herpes simplex virus 1; herpes simplex virus 2; host organism interaction; immunocytochemistry; keratitis; laboratory mouse; latent virus infection; mutant; neurotropic virus; ocular herpes; open reading frames; recombinant virus; site directed mutagenesis; tissue /cell culture; virion; virus RNA; virus cytopathogenic effect; virus genetics; virus protein

DESCRIPTION (from abstract): Herpes simplex virus (HSV) keratitis is a leading cause of non-traumatic blindness in the US, with more than 200,000 cases per year. HSV can cause a variety of ocular diseases in humans ranging from self-limiting dendritic epithelial keratitis, conjunctivitis, and blepharitis to necrotizing stromal keratitis. In addition, HSV commonly causes cold sores, genital sores, and is a leading cause of viral encephalitis. The life cycles of HSV and other neurotropic herpesviruses are characterized by a lytic phase of infection at peripheral sites such as the cornea and skin during which all virus genes are expressed, and a latent phase of infection in neurons, during which gene expression is extremely limited. Latency represents a lifelong source of virus which can reactivate periodically causing severe ocular and other mucocutaneous damage, and the ability to establish lifelong latency renders HSV resistant to cure. One hallmark of the neurotropic herpesviruses is their ability to rapidly shut off macromolecular synthesis in the cells that they infect. It has been shown for HSV type 1 (HSV-1) that the gene responsible for this shut off is the product of the UL41 gene known as the virion host shutoff protein or vhs. Vhs is an important determinant of pathogenicity, allowing the virus to replicate to high titers in the cornea in vivo, to damage the cornea, and to establish latency with high efficiency. The objectives of this proposal are to investigate further the mechanisms of action and functions of the vhs protein in vivo. To this end, mutations will be introduced into the open reading frame of vhs as well as into other genes which are required for and associated with vhs activity. In addition, intertypic and interstrain recombinants will be generated in which vhs is exchanged from one virus to another. The effect of these mutations and exchanges upon the ability of the virus to induce degradation of host and viral mRNAs will then be measured by in vitro express/degradation assays and in vivo following introduction of these mutations into the context of the viral genome. Resulting mutants will also be tested for their ability to establish, maintain, and reactivate from viral latency in neurons. Efforts will also be made to assess the role of vhs in the induction of corneal damage and the role of interferons in limiting corneal disease. A better understanding of vhs will allow further insight into the mechanisms by which HSV can persist for the lifetime of its host and indicate novel therapeutic approaches and targets for control of this blinding disease.

描述（摘要）：单纯疱疹病毒（HSV）角膜炎是 美国非创伤失明的主要原因，超过200,000 每年案件。 HSV可能引起人类各种眼部疾病 从自限制的树突状上皮角膜炎，结膜炎， 和骨炎可坏死的基质角膜炎。 另外，HSV通常 引起唇疱疹，生殖疮，是病毒的主要原因 脑炎。 HSV和其他神经疱疹病毒的生命周期 其特征是在外周部位的感染阶段（例如 所有病毒基因都表达的角膜和皮肤和潜在 神经元感染阶段，在此期间基因表达极为 有限的。 潜伏期代表可以重新激活的病毒的终生来源 定期造成严重的眼和其他粘膜皮肤损伤，并 能够建立终身潜伏期的能力使HSV具有耐药性。 神经疱疹病毒的一个标志是它们快速的能力 关闭其感染细胞中的大分子合成。 它有 已显示HSV类型1（HSV-1）的基因负责此封闭的基因 OFF是UL41基因称为Virion宿主关闭蛋白的产物 或VHS。 VHS是致病性的重要决定因素，允许 病毒复制到体内角膜的高滴度，损坏 角膜，并以高效率建立潜伏期。 该提议的目标是进一步研究 VHS蛋白在体内的作用和功能。 为此，突变 将被引入VHS的开放阅读框架以及其他 与VHS活性相关的基因。 此外， 将生成型中型和跨界重组因素，在其中VHS为 从一种病毒交换到另一种病毒。 这些突变的影响和 交流病毒诱导宿主降解的能力和 然后，病毒mRNA将通过体外表达/降解测定和 在将这些突变引入到背景下的体内 病毒基因组。 结果突变体还将测试其能力 从神经元的病毒潜伏期中建立，维持和重新激活。 努力 还将制定评估VHS在角膜诱导中的作用 损害和干扰素在限制角膜疾病中的作用。 更好 对VHS的理解将使您可以进一步了解其机制 HSV可以在其宿主的一生中持续存在，并表明新颖的治疗性 控制这种盲目疾病的方法和目标。