Varicella-zoster Virus: Tegument Proteins in Pathogenesis

水痘带状疱疹病毒：发病机制中的皮层蛋白

基本信息

批准号：
8121089
负责人：
Ann Arvin
金额：
$ 7.4万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-16 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8121089
关键词：
Address Adult Afferent Neurons Animal Model Apoptosis Attenuated Autopsy Binding Binding Sites Cell Culture Techniques Cells Chemical Agents Chickenpox Child Disease Elderly Elements Ensure Equilibrium Evaluation Event Exhibits Ganglia Generations Genes Genetic Transcription Genome Glycoproteins Goals Grant Heating Herpes zoster disease Herpesviridae Herpesvirus Type 3 Histone Deacetylase Inhibitor Human Immune Immune system In Vitro Infection Inhibition of Apoptosis Interferons Licensing Life Lytic Phase Maps Mediating Membrane Proteins Methods Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Myxoid cyst Nerve Growth Factors Neuroglia Neurons Neuropathogenesis Neurotropism Nuclear Nuclear Envelope Pathogenesis Peripheral Phosphorylation Phosphotransferases Population Process Production Progress Reports Protein Kinase Proteins Public Health Recombinant Vaccines Recombinants Regulation Reporter Role Sensory Ganglia Severe Combined Immunodeficiency Signal Transduction Simplexvirus Site Skin Spinal Ganglia Staging Stimulus Study models T-Lymphocyte Testing Time Tissues Trans-Activators Transcript Tropism United States Vaccines Variant Viral Viral Genes Viral Proteins Virion Virulence Virus Virus Diseases Virus Replication Work Xenograft procedure design genetic regulatory protein high risk improved in vivo in vivo Model mutant neuron apoptosis neurovirulence prevent promoter protein expression reactivation from latency research study response satellite cell skin xenograft stressor success transcription factor viral DNA virus pathogenesis

项目摘要

Varicella zoster virus (VZV) causes varicella during primary infection, persists in sensory ganglia and may reactivate from latency to cause zoster. VZV pathogenesis depends upon its tropisms for T cells, skin and sensory ganglia. VZV vaccines to prevent varicella and to reduce zoster morbidity in the elderly are very effective. However, VZV control could be improved with a 2nd generation recombinant vaccine that has attenuated replication in skin, but limited infectivity for T cells and ganglia. VZV infection of sensory ganglia ensures its survival in the human population through reactivations from latency that result in zoster. We have developed a model for studying VZV neuropathogenesis by making xenografts of human dorsal root ganglia (DRG) in mice with severe combined immunodeficiency (SCID). Our analyses of VZV tegument/regulatory proteins will be extended to examine their functions in VZV neurotropism. We will focus on IE63, an important immediate early regulatory protein encoded by ORF63, and the ORF66 kinase protein using VZV recombinants that have targeted mutations in these genes. The SCIDhu DRG model also offers unique opportunities to investigate how cell transactivators that modulate viral gene promoters may control VZV neurotropism and to identify what perturbations of persistently infected neurons may trigger of VZV reactivation. The roles of IE63 and ORF66 at early and late stages of VZV infection of ganglia will be examined in SCIDhu DRG. Experiments will address four general hypotheses: 1) initial VZV replication is required for, or influences the level of persistent VZV DNA copies in neurons; 2) VZ virions must be made and released efficiently; 3) VZV proteins that inhibit neural cell apoptosis facilitate persistence; 4) VZV infection of DRG reflects an equilibrium with innate cellular responses, mediated by interferons (IFN), which optimizes persistence. VZV gene promoters, like those of all herpesviruses, have elements that are recognized by ubiquitous host cell regulatory proteins. Our hypothesis is that cellular proteins regulate transcription from the critical ORF63 promoter during initial infection and are needed for the transition to latency in sensory neurons. Experiments to understand what cellular stressors may induce VZV reactivation from persistently infected DRG will examine heat, chemical agents, histone deacetylase inhibitors, interference with nerve growth factor signaling and other triggers known to enhance herpes simplex virus reactivation. The work proposed for Yr. 1 and Yr. 2 (see Specific Aims) is expected to yield new information about the molecular mechanisms of VZV neuropathogenesis in differentiated peripheral neurons and satellite cells within human sensory ganglia and to identify options for designing a 2nd generation VZV vaccine with genetic changes that have been proved to reduce virulence in the SCIDhu DRG model in vivo.

水痘带状疱疹病毒（VZV）在原发性感染期间引起水疗，感觉神经节持续存在可能会从潜伏期重新激活引起带状绳。 VZV发病机理取决于其对T细胞的偏见，皮肤和感官神经节。 VZV疫苗可以防止水痘并降低老年的带状疱疹发病率非常有效。但是，通过具有第二代重组疫苗可以改善VZV控制皮肤中的复制减弱，但T细胞和神经节的感染力有限。感官神经节感染的VZV感染通过导致带状线的潜伏期的重新激活来确保其在人口中的生存。我们已经开发了一种通过使人体根部的异种移植物来研究VZV神经病发生的模型严重合并免疫缺陷（SCID）的小鼠中的神经节（DRG）。我们对VZV的分析 TEGUMENT/调节蛋白将扩展以检查其在VZV神经质主义中的功能。我们将集中精力在IE63上，这是一个由ORF63编码的重要早期调节蛋白，ORF66激酶使用具有这些基因突变的VZV重组剂的蛋白质。 Scidhu DRG模型提供了独特的机会来研究调节病毒基因启动子的细胞反式激活因子如何控制VZV神经性和确定持续感染神经元的扰动可能会触发 VZV重新激活。 IE63和ORF66在VZV感染的早期和晚期的角色将是在Scidhu Drg中进行了检查。实验将解决四个一般假设：1）初始VZV复制是需要或影响神经元中持续的VZV DNA副本的水平； 2）必须制作VZ病毒体并有效释放； 3）抑制神经细胞凋亡的VZV蛋白促进持久性； 4）VZV DRG的感染反映了具有先天细胞反应的平衡，由干扰素（IFN）介导，该反应优化持久性。 VZV基因启动子像所有疱疹病毒一样，具有元素被普遍存在的宿主细胞调节蛋白识别。我们的假设是细胞蛋白调节在初始感染期间，从关键ORF63启动子进行转录，需要过渡到感觉神经元的延迟。实验了解哪些细胞应激源可能诱导VZV重新激活从持续感染的DRG中，将检查热量，化学剂，组蛋白脱乙酰基酶抑制剂，干扰神经生长因子信号传导和其他已知可增强疱疹单纯疱疹病毒的触发因素重新激活。建议的工作。 1和年。 2（请参阅特定目的）有望产生新信息关于分化的周围神经元和VZV神经病发生的分子机制人类感觉神经节内的卫星细胞，并确定设计第二代vzv的选项事实证明，具有遗传变化的疫苗可降低体内Scidhu DRG模型中的毒力。