Genetic analysis of Herpes virus neurotropism and encephalitis

疱疹病毒嗜神经性和脑炎的遗传分析

基本信息

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
项目类别：
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

项目摘要

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）感染负责复发性角膜毛发性角膜炎以及孢子的急性急性脑炎。即使进行抗病毒治疗，HSV脑炎后死亡率或严重神经缺陷的发生率仍然很高。我们的长期目标是确定促进HSV传播到中枢神经系统的病毒和感染的宿主蛋白。使用一种新型的体内小鼠视网膜神经节细胞模型，我们发现HSV病毒蛋白US9对于长距离传播的病毒核蛋白质和病毒DNA是从感染的神经元细胞体朝轴突末端传播的。了解病毒靶向输送的基础机制直接导致识别HSV和其他神经性病毒感染（例如CMV和VZV）中脆弱的步骤。现在，我们建议定义US9的区域，这些区域对于有效的Nucleocapsid分选是必要的。我们还将定义与感染轴突中US9相关的病毒蛋白和宿主蛋白。最后，我们将使用新颖的微观培养系统测试病毒和宿主运动蛋白在感染轴突中递送核素的功能。了解成熟神经元中病毒的病理生理学很重要，因为神经元之间HSV传播的机制对于开发新的抗病毒药物的发展至关重要，从而阻止病毒性脑蔓延。此外，我们对HSV传播的了解将与对其他病毒感染作斗争至关重要。公共卫生相关性：单纯疱疹1型（HSV）和2型疱疹造成了大多数疱疹性脑炎病例。 HSV也是导致眼部疱疹性角膜炎角膜上皮的复发性疤痕的病原体，这是失明的常见原因。 HSV可以在感染的神经元中潜在潜在，并且可以对阿昔洛韦和阿司可衍生药物的治疗具有抵抗力。因此，对病毒感染感觉神经元和前往中枢神经系统的机制的探索是有价值的，因为它将洞悉可通过治疗的病原体的潜在脆弱性。