Investigation of herpes simplex virus -1 neurotropism in SCID DRG xenografts

SCID DRG 异种移植物中单纯疱疹病毒-1 向神经性的研究

基本信息

批准号：
7847594
负责人：
Ann Arvin
金额：
$ 23.95万
依托单位：
STANFORD UNIVERSITY
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：
2009-05-22 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847594
关键词：
Address Afferent Neurons Animal Model Antiviral Agents Attenuated Axonal Transport Benign Biology Cell Communication Cells Characteristics Chemicals Disease Double Stranded DNA Virus Encephalitis Epithelial Cells Evaluation Event Exhibits Failure G0 Phase Ganglia Gene Expression Genes Genetic Transcription Genital system Genome Glycoproteins Goals Herpesviridae Herpesvirus 1 Herpesvirus Type 3 Human Human Herpesvirus 2 Immune system Immunocompromised Host Individual Infection Investigation Lesion Life Lytic Methods Modeling Molecular Mucous Membrane Mus Mutation Myxoid cyst Nerve Fibers Neuroglia Neurons Neuropathogenesis Neurotropism Oral Oryctolagus cuniculus PVRL1 Patients Pattern Peripheral Nerves Pharmaceutical Preparations Public Health Recombinants Replication Initiation Rest Reverse Transcriptase Polymerase Chain Reaction Rodent Model Sensory Ganglia Severe Combined Immunodeficiency Signal Pathway Signal Transduction Simplexvirus Site Skin Specimen Spinal Ganglia Stimulus Surface System Thymidine Kinase Tissues Transcript United States Vaccines Viral Viral Genes Viral Genome Viral Proteins Virion Virus Virus Latency Work Xenograft Model Xenograft procedure afferent nerve anterograde transport cell type gene function high risk high voltage electron microscopy human disease in vivo insight latency associated transcript latent infection mouse model mutant neonate neuronal cell body neurovirulence prevent protein expression public health relevance receptor recombinant virus research study response satellite cell stressor vaccine candidate virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus-1 (HSV-1) is human alphaherpesvirus that establishes a lifelong latent infection in peripheral nerve ganglia following primary infection. HSV-1 infections are generally benign, although its capacity for neurovirulence and neuroinvasiveness are the primary mechanisms through which HSV-1 can cause harmful disease in humans, especially in neonates and immunocompromised hosts. Our overall objective is to develop a model for examining HSV-1 neuropathogenesis in human sensory ganglia in vivo. We will evaluate HSV-1 infection of human dorsal root ganglion (DRG) xenografts in mice with severe combined immunodeficiency (SCID), exploiting the system that we created to investigate varicella- zoster virus (VZV) neuropathogenesis. The biology of HSV-1 infection is similar to VZV in that both HSV-1 and VZV establish latency within sensory ganglia following primary infection. Studies of VZV in the SCIDhu DRG model have provided the first opportunity to examine replication of a human alphaherpesvirus within cells that comprise human DRG in vivo. The DRG xenograft model has the potential to reveal characteristics of HSV-1 neuropathogenesis in the natural human host tissue microenvironment in vivo in an experimental system that will add substantially to observations from rodent models. Experiments will address three specific aims: (1) we will define the course of events that follows HSV-1 inoculation of human DRG xenografts in SCID mice, identifying what cell types within DRG are permissive for HSV-1 gene expression, whether neurons and/or satellite cells become productively infected and whether HSV-1 undergoes the pattern of transition to persistence in human neurons that we have observed in VZV-infected DRG xenografts; (2) we will investigate HSV-1 gene functions through the evaluation of recombinant HSV-1 strains, in particular we will examine the requirement for HSV-1 thymidine kinase (TK) during initial infection and persistence in DRG, and gD mutants for their capacity for viral entry; (3) if HSV-1 is shown to establish persistence in DRG xenografts, we will assess whether this model can be used to study HSV-1 reactivation by explanting latently-infected DRG xenografts and treating with agents that trigger neural cell signaling pathways and increase HSV-1 reactivation in rodent models. This work is intended to demonstrate the feasibility of using DRG xenografts in SCID mice to explore the molecular mechanisms of HSV-1 neuropathogenesis in differentiated human sensory neurons and non-neuronal cells within their sensory ganglia tissue microenvironment in vivo. In addition to new insights about basic virus-host interactions, such a model has potential value for studying antiviral drugs and live attenuated HSV-1 vaccine candidates to treat or prevent human disease caused by this common virus. PUBLIC HEALTH RELEVANCE: Herpes Simplex Virus 1 (HSV-1) causes oral and genital lesions and encephalitis. These infections remain an important public health problem in the United States. Serious complications from HSV-1 can occur in healthy people and in those who have diseases that impair their immune systems. Our goal is to develop a model to study how HSV-1 infects human nerve cells that will have potential value for developing new drugs and vaccines.

描述（由申请人提供）：单纯疱疹病毒-1（HSV-1）是人αHerpesvirus，在初次感染后，在周围神经神经节中建立了终生的潜在感染。 HSV-1感染通常是良性的，尽管其神经动力和神经侵袭的能力是HSV-1可以在人类中引起有害疾病的主要机制，尤其是在新生儿和免疫强化宿主中。我们的总体目标是开发一个模型，用于检查体内人类感觉神经节中HSV-1神经病的发生。我们将评估患有严重合并免疫缺陷（SCID）的小鼠中人背根神经节（DRG）异种移植物的HSV-1感染，利用了我们创建的系统来研究水痘带状疱疹病毒（VZV）神经疾病的发生。 HSV-1感染的生物学类似于VZV，因为HSV-1和VZV在原发性感染后都在感觉神经节内建立潜伏期。 Scidhu DRG模型中VZV的研究为检查构成人体DRG的细胞中人αHerpeSvior的复制提供了第一个机会。 DRG异种移植模型具有揭示自然人类宿主组织微环境体内天然宿主组织微环境在实验系统中的特征，该系统将大大增加啮齿动物模型的观察结果。实验将针对三个具体目标：（1）我们将定义SCID小鼠中HSV-1接种HSV-1接种后的事件的过程，确定DRG中DRG中的哪些细胞类型允许HSV-1基因表达，是否神经元和////////或卫星细胞被有效地感染，以及HSV-1是否经历了我们在VZV感染的DRG异种移植物中观察到的人类神经元中持久性的过渡模式；（2）我们将通过评估重组HSV-1菌株来研究HSV-1基因的功能，特别是我们将在初始感染和DRG中检查HSV-1胸苷激酶（TK）的需求，而GD突变体的GD突变体的需求病毒进入的能力；（3）如果显示出HSV-1在DRG异种移植物中建立持久性，我们将评估该模型是否可以通过探索潜在感染的DRG异种移植物来研究HSV-1重新激活，并用触发神经细胞信号通路并增加的药物治疗啮齿动物模型中的HSV-1重新激活。这项工作旨在证明在SCID小鼠中使用DRG异种移植物探索分化的人类感觉神经元和非神经神经神经神经神经神经神经节组织中的无神经元细胞中HSV-1神经病生成的分子机制的可行性。除了有关基本病毒宿主相互作用的新见解外，这种模型还具有潜在的研究抗病毒药和候选HSV-1疫苗的潜在价值，可以治疗或预防由这种常见病毒引起的人类疾病。公共卫生相关性：单纯疱疹病毒1（HSV-1）引起口腔和生殖器病变和脑炎。在美国，这些感染仍然是一个重要的公共卫生问题。 HSV-1的严重并发症可能在健康的人和患有损害其免疫系统的疾病的患者中发生。我们的目标是开发一个模型，以研究HSV-1如何感染人类神经细胞，该神经细胞将对开发新药和疫苗具有潜在的价值。