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: 7849349
• 负责人: JENNIFER Hart LAVAIL
• 金额: $ 1.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849349
• 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（由申请方提供）：单纯疱疹病毒（HSV）感染是复发性角膜疱疹性角膜炎以及散发性急性脑炎的原因。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。我们的长期目标是鉴定促进HSV传播到中枢神经系统的病毒和感染宿主蛋白。使用一种新的在体内小鼠视网膜神经节细胞模型，我们已经发现，HSV病毒蛋白，Us9，是必要的长距离传播，特别是病毒核衣壳和病毒DNA从感染的神经元细胞体向轴突终端。了解病毒靶向递送的机制直接导致HSV和其他嗜神经病毒感染（如CMV和VZV）中脆弱步骤的鉴定。我们现在建议定义Us9的区域，这些区域对于有效的核衣壳分选是必要的。我们还将定义与感染轴突中的Us9相关的病毒蛋白和宿主蛋白。最后，我们将测试病毒和宿主马达蛋白的功能，在感染的轴突内使用一种新的，微型培养系统的核衣壳的交付。了解病毒在成熟神经元中的病理生理学是重要的，因为神经元之间HSV传播的机制对于开发阻断病毒脑炎传播的新抗病毒药物至关重要。此外，我们对HSV传播的了解将与对抗其他病毒感染有关。公共卫生相关性：1型单纯疱疹病毒（HSV）和2型是大多数疱疹性脑炎病例的原因。HSV也是导致眼疱疹性角膜炎（一种常见的致盲原因）中角膜上皮复发性瘢痕形成的病原体。HSV可以潜伏在受感染的神经元中，并且可以对阿昔洛韦和阿昔洛韦衍生药物的治疗产生耐药性。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，因为它将提供对病原体潜在脆弱性的深入了解，可以在治疗上加以利用。