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：
7638379
负责人：
Ann Arvin
金额：
$ 20.19万
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/7638379
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）是人类α疱疹病毒，在初次感染后在周围神经节中建立终生潜伏感染。 HSV-1 感染通常是良性的，尽管其神经毒力和神经侵袭能力是 HSV-1 在人类（尤其是新生儿和免疫功能低下的宿主）中引起有害疾病的主要机制。我们的总体目标是开发一种模型来检查体内人类感觉神经节的 HSV-1 神经发病机制。我们将利用我们创建的用于研究水痘带状疱疹病毒（VZV）神经发病机制的系统，评估患有严重联合免疫缺陷（SCID）小鼠的人背根神经节（DRG）异种移植物的HSV-1感染。 HSV-1 感染的生物学特性与 VZV 相似，HSV-1 和 VZV 均在初次感染后在感觉神经节内建立潜伏期。 SCIDhu DRG 模型中的 VZV 研究首次提供了在体内检查人类 α 疱疹病毒在构成人类 DRG 的细胞内复制的机会。 DRG异种移植模型有可能在实验系统中揭示自然人类宿主组织微环境中HSV-1神经发病机制的特征，这将大大增加啮齿动物模型的观察结果。实验将解决三个具体目标：（1）我们将定义 SCID 小鼠中人类 DRG 异种移植物 HSV-1 接种后的事件过程，确定 DRG 内的哪些细胞类型允许 HSV-1 基因表达，无论是神经元还是/或卫星细胞被有效感染，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续存在的转变模式； (2)我们将通过评估重组HSV-1毒株来研究HSV-1基因功能，特别是我们将检查HSV-1胸苷激酶（TK）在初始感染和在DRG中持续存在期间的需求，以及gD突变体的其功能。病毒进入的能力； (3)如果HSV-1被证明在DRG异种移植物中建立持久性，我们将评估该模型是否可用于通过外植潜伏感染的DRG异种移植物并用触发神经细胞信号传导途径并增加啮齿动物模型中 HSV-1 的重新激活。这项工作旨在证明在 SCID 小鼠中使用 DRG 异种移植物来探索体内感觉神经节组织微环境中分化的人类感觉神经元和非神经元细胞中 HSV-1 神经发病机制的可行性。除了关于基本病毒与宿主相互作用的新见解外，这种模型对于研究抗病毒药物和 HSV-1 减毒活疫苗候选物具有潜在价值，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) 会导致口腔和生殖器病变以及脑炎。这些感染仍然是美国的一个重要公共卫生问题。 HSV-1 引起的严重并发症可能发生在健康人和患有损害免疫系统疾病的人身上。我们的目标是开发一个模型来研究 HSV-1 如何感染人类神经细胞，这对于开发新药和疫苗具有潜在价值。