Genetic analysis of Herpes virus neurotropism and encephalitis

疱疹病毒嗜神经性和脑炎的遗传分析

• 批准号: 7678405
• 负责人: JENNIFER Hart LAVAIL
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678405
• 关键词: Acute; Acyclovir; Adaptor Signaling Protein; Afferent Neurons; Antiviral Agents; Axon; Axonal Transport; Blindness; Capsid; Capsid Proteins; Cell model; Cells; Cicatrix; Cornea; Cytomegalovirus; DNA; Dependence; Development; Encephalitis; Functional disorder; Goals; Herpes Simplex Infections; Herpes encephalitis; Herpesviridae; Herpesvirus 1; Herpetic Keratitis; Human Herpesvirus 2; Incidence; Infection; Kinesin; Kinetics; Learning; Link; Motor; Mus; Neuraxis; Neurologic; Neurons; Neurotropism; Nucleocapsid; Pharmaceutical Preparations; Presynaptic Terminals; Proteins; Recurrence; Resistance; Retinal Ganglion Cells; Role; Simplexvirus; Sorting - Cell Movement; System; Testing; Travel; Viral; Viral Proteins; Virus; Virus Diseases; anterograde transport; corneal epithelium; fighting; genetic analysis; in vitro Assay; in vivo; insight; knock-down; mortality; neuronal cell body; neurotropic; novel; pathogen; protein expression; public health relevance; research study; retinal axon; small hairpin RNA; targeted delivery; transmission process; viral DNA

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) infections are responsible for recurrent corneal herpetic keratitis, as well as sporatic acute encephalitis. Even with antiviral treatment, the incidence of mortality or severe neurological deficits after HSV encephalitis remains high. Our long-term goal is to identify the viral and infected host proteins that promote the spread of HSV into the central nervous system. Using a novel in vivo mouse retinal ganglion cell model, we have found that the HSV viral protein, Us9, is necessary for the long distance spread specifically of viral nucleocapsid and viral DNA from an infected neuron cell body toward the axon terminal. Understanding the mechanisms underlying targeted delivery of virus leads directly to the identification of vulnerable steps in HSV and other neurotropic viral infections, such as CMV and VZV. We now propose to define the regions of the Us9 that are necessary for efficient nucleocapsid sorting. We shall also define the viral proteins and host proteins that associate with Us9 in infected axons. Lastly, we shall test the function of virus and host motor proteins in the delivery of nucleocapsids within an infected axon using a novel, microscale culture system. Understanding the pathophysiology of the virus in mature neurons is important, because the mechanisms of HSV transmission between neurons is essential for development of new antiviral drugs that block viral encephalitic spread. In addition, what we learn about HSV transmission will be relevant for fighting other virus infections. PUBLIC HEALTH RELEVANCE: Herpes simplex type 1 (HSV) and type 2 are responsible for the majority of herpetic encephalitis cases. HSV is also the pathogen responsible for recurrent scarring of the corneal epithelium in ocular herpetic keratitis, a common cause of blindness. HSV can become latent in infected neurons and can become resistant to treatment with acyclovir and acyclovir-derived drugs. Thus, exploration of the mechanisms used by the virus to infect sensory neurons and travel to the central nervous system is of value in that it will provide insight into potential vulnerabilities of the pathogen that can be exploited therapeutically.

描述（由申请人提供）：单纯疱疹病毒（HSV）感染导致复发性角膜疱疹性角膜炎以及散发性急性脑炎。即使进行抗病毒治疗，HSV 脑炎后死亡率或严重神经功能缺损的发生率仍然很高。我们的长期目标是识别促进 HSV 传播到中枢神经系统的病毒和感染宿主蛋白。使用新型体内小鼠视网膜神经节细胞模型，我们发现HSV病毒蛋白Us9对于病毒核衣壳和病毒DNA从受感染的神经元细胞体向轴突末端的长距离传播是必需的。了解病毒靶向传递的机制可以直接识别 HSV 和其他嗜神经病毒感染（例如 CMV 和 VZV）中的脆弱步骤。我们现在建议定义有效核衣壳分选所必需的 Us9 区域。我们还将定义与受感染轴突中的 Us9 相关的病毒蛋白和宿主蛋白。最后，我们将使用新型微型培养系统测试病毒和宿主运动蛋白在受感染轴突内递送核衣壳的功能。了解成熟神经元中病毒的病理生理学非常重要，因为神经元之间 HSV 传播的机制对于开发阻止病毒性脑炎传播的新型抗病毒药物至关重要。此外，我们对单纯疱疹病毒传播的了解也将有助于对抗其他病毒感染。公共卫生相关性：大多数疱疹性脑炎病例是由 1 型单纯疱疹 (HSV) 和 2 型引起的。 HSV 也是引起眼疱疹性角膜炎（失明的常见原因）中角膜上皮复发性疤痕的病原体。 HSV 可在受感染的神经元中潜伏，并对阿昔洛韦和阿昔洛韦衍生药物产生耐药性。因此，探索病毒感染感觉神经元并传播到中枢神经系统的机制是有价值的，因为它将提供对可用于治疗的病原体的潜在脆弱性的深入了解。