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.

简介(摘自)：单纯疱疹病毒(HSV)角膜炎是一种 美国非外伤性失明的主要原因，有20多万人 每年的病例数。单纯疱疹病毒可导致人类多种眼部疾病 从自限性树突状上皮角膜炎，结膜炎， 以及眼缘炎到坏死性间质角膜炎。此外，单纯疱疹病毒通常 会导致唇疱疹、生殖器溃疡，并且是病毒传播的主要原因。 脑炎。单纯疱疹病毒等嗜神经性疱疹病毒的生活史 其特征是周围部位的感染处于裂解期 所有病毒基因表达的角膜和皮肤，以及潜伏的 神经细胞的感染阶段，在此期间基因表达极端 有限的。潜伏期代表可重新激活的终生病毒源 周期性地造成严重的眼部和其他黏膜皮肤损害，以及 建立终生潜伏期的能力使HSV对治愈产生抵抗力。 嗜神经性疱疹病毒的一个特点是它们能够迅速 切断它们感染的细胞中的大分子合成。它有 对于1型单纯疱疹病毒(HSV-1)来说，导致这种关闭的基因已经被证明 Off是被称为病毒粒子宿主关闭蛋白的UL41基因的产物 或者录像机。VHS是致病性的重要决定因素，使 病毒在体内的角膜中复制到高滴度，以破坏 角膜，并高效地建立潜伏期。 这项建议的目的是进一步调查 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 VHS活动所需并与之相关的基因。此外, 将产生VHS的类型间和菌株间重组体 从一种病毒传播到另一种病毒。这些突变的影响和 关于病毒诱导宿主和 然后将通过体外表达/降解分析和 在体内，在将这些突变引入到 病毒基因组。由此产生的突变体也将接受测试，以确定它们是否有能力 在神经元中建立、维持和重新激活病毒潜伏期。努力 也将评估VHS在角膜诱导中的作用 干扰素的损害和在限制角膜疾病中的作用。更好的 对VHS的理解将使我们能够进一步深入了解VHS HSV可以在宿主的一生中持续存在，并预示着新的治疗方法 控制这种致盲疾病的方法和目标。