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:
  • 金额:
    $ 7.4万
  • 依托单位:
  • 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

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)在初次感染时引起水痘,持续存在于感觉神经节和 可从潜伏期重新激活以引起带状疱疹。VZV的致病机制取决于其对T细胞、皮肤的趋向性 和感觉神经节。预防老年人水痘和减少带状疱疹发病率的VZV疫苗是 非常有效。然而,第二代重组疫苗可以改善VZV的控制 减弱了皮肤的复制,但对T细胞和神经节的感染性有限。感觉神经节VZV感染 通过从导致带状疱疹的潜伏期重新激活来确保其在人类种群中的生存。我们 通过制作人背根异种移植,建立了研究VZV神经发病机制的模型 严重联合免疫缺陷(SCID)小鼠的神经节(DRG)。我们对VZV的分析 被膜/调节蛋白将被扩展以研究它们在VZV神经趋向性中的功能。我们将专注于 在IE63上,ORF63编码的一个重要的即刻早期调控蛋白和ORF66激酶 使用在这些基因中具有靶向突变的VZV重组体的蛋白质。SCIDhu DRG模型还 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的神经趋向性,并确定持续感染的神经元可能触发的扰动 VZV重新激活。IE63和ORF66在VZV感染神经节早期和晚期的作用 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拷贝水平;2)必须制造VZ病毒粒子 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感染反映了由干扰素(干扰素)介导的先天细胞反应的平衡, 优化持久性。像所有疱疹病毒一样,VZV基因启动子具有 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 在初始感染过程中从关键的ORF63启动子转录,并在向 感觉神经元的潜伏期。了解什么细胞应激源可能导致VZV重新激活的实验 从持续感染的DRG将检查热,化学制剂,组蛋白去乙酰酶抑制剂, 干扰神经生长因子信号和其他已知可增强单纯疱疹病毒的触发因素 重新激活。这项工作是为您提出的。1和Yr.2(见具体目标)预计将产生新的信息 关于VZV在分化的外周神经元中神经致病的分子机制 人类感觉神经节内的卫星细胞,并确定设计第二代VZV的选择 具有基因变化的疫苗已被证明在体内SCIDhu DRG模型中降低了毒力。

项目成果

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Ann Arvin其他文献

Ann Arvin的其他文献

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{{ truncateString('Ann Arvin', 18)}}的其他基金

Varicella zoster virus: molecular controls of cell fusion-dependent pathogenesis
水痘带状疱疹病毒:细胞融合依赖性发病机制的分子控制
  • 批准号:
    8663185
  • 财政年份:
    2012
  • 资助金额:
    $ 7.4万
  • 项目类别:
Varicella zoster virus: molecular controls of cell fusion-dependent pathogenesis
水痘带状疱疹病毒:细胞融合依赖性发病机制的分子控制
  • 批准号:
    8472440
  • 财政年份:
    2012
  • 资助金额:
    $ 7.4万
  • 项目类别:
Varicella zoster virus: molecular controls of cell fusion-dependent pathogenesis
水痘带状疱疹病毒:细胞融合依赖性发病机制的分子控制
  • 批准号:
    8401103
  • 财政年份:
    2012
  • 资助金额:
    $ 7.4万
  • 项目类别:
Protective Immunity Against Herpesvirus Infections
针对疱疹病毒感染的保护性免疫
  • 批准号:
    8260368
  • 财政年份:
    2011
  • 资助金额:
    $ 7.4万
  • 项目类别:
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
  • 批准号:
    7638379
  • 财政年份:
    2009
  • 资助金额:
    $ 7.4万
  • 项目类别:
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
  • 批准号:
    7847594
  • 财政年份:
    2009
  • 资助金额:
    $ 7.4万
  • 项目类别:
CD8 T cell Immunity to Influenza
CD8 T 细胞对流感的免疫
  • 批准号:
    7657178
  • 财政年份:
    2008
  • 资助金额:
    $ 7.4万
  • 项目类别:
Pilot Projects Component (Pilot Proj 2: Guccione)
试点项目组件(试点项目 2:Guccione)
  • 批准号:
    7657168
  • 财政年份:
    2008
  • 资助金额:
    $ 7.4万
  • 项目类别:
Protective Immunity Against Herpesvirus Infections
针对疱疹病毒感染的保护性免疫力
  • 批准号:
    7212913
  • 财政年份:
    2007
  • 资助金额:
    $ 7.4万
  • 项目类别:
ANTIVIRAL IMMUNE MECHANISMS IN EARLY CHILDHOOD
幼儿期的抗病毒免疫机制
  • 批准号:
    7202035
  • 财政年份:
    2004
  • 资助金额:
    $ 7.4万
  • 项目类别:

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