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首页> 外文学位 >Analysis of the transcription of immediate early regulatory genes of Varicella-Zoster virus and host cell gene expression in VZV-infected cells in vitro and in the SCIDhu mouse model in vivo.
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Analysis of the transcription of immediate early regulatory genes of Varicella-Zoster virus and host cell gene expression in VZV-infected cells in vitro and in the SCIDhu mouse model in vivo.

机译：水痘带状疱疹病毒的早期早期调控基因的转录和体外感染VZV的细胞以及体内SCIDhu小鼠模型中宿主细胞基因表达的分析。

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摘要

Varicella-zoster virus (VZV) is a human alphaherpesvirus that causes varicella and herpes zoster. Infection begins with virus entry through the mucosa of the upper respiratory tract, leading to primary viremia and spread of virus by infected T cells to skin, where the virus causes a rash, followed by infection of sensory ganglia, where the virus establishes latency. This work characterizes the host response to VZV infection in cells that are biologically important during VZV pathogenesis, and examines the contribution of specific viral proteins to VZV pathogenesis. Using microarray technology, the host cell transcriptional response to VZV infection was found to be distinct in VZV-infected primary human fibroblasts and T cells in culture, and human skin xenografts in the SCIDhu mouse model. VZV genes were added to the human cDNA microarrays and viral gene transcription was monitored in primary fibroblasts. Infection with a virus containing a point mutation in the IE63 protein resulted in the decreased transcription of several viral genes. The host cell response to infection with this, or another small plaque phenotype mutant virus, was similar to infection with intact VZV, suggesting that the small plaque phenotype resulted from deficiencies in viral gene expression rather than differing host cell responses to the viruses. Transcription of ORF62 and ORF63, which encode the immediate early regulatory proteins IE62 and IE63, was analyzed by cloning the 1.5kb ORF62/63 intergenic region between two different luciferase genes, which acted as reporters for ORF62 or ORF63 expression. This reporter cassette was inserted into the viral genome so that the transcription of ORF62 and ORF63 could be monitored during VZV infection without affecting the growth of the virus. Mutations of binding sites for cellular transregulatory proteins were found to alter the luciferase activity of either or both the ORF62 and ORF63 reporters in fibroblasts. The microarray results also indicated that viral infection altered the regulation of specific host cell signaling pathways, including the inhibition of the NF-kappaB pathway. This pathway, which mediates an inflammatory response to infection, was inhibited by the VZV-induced stabilization of IkappaBalpha levels and the associated cytoplasmic sequestration of NF-kappaB proteins in infected cells.
机译：水痘带状疱疹病毒（VZV）是一种人类α疱疹病毒，可引起水痘和带状疱疹。感染始于病毒通过上呼吸道粘膜进入，导致原发病毒血症，并通过被感染的T细胞将病毒传播到皮肤，在那里病毒引起皮疹，随后感染感觉神经节，在病毒中建立潜伏期。这项工作表征宿主对VZV发病机理在生物学上重要的细胞中VZV感染的反应，并研究特定病毒蛋白对VZV发病机理的作用。使用微阵列技术，发现宿主细胞对VZV感染的转录反应在培养的VZV感染的原代人成纤维细胞和T细胞中以及在SCIDhu小鼠模型中的人皮肤异种移植物中是不同的。将VZV基因添加到人cDNA微阵列中，并在原代成纤维细胞中监测病毒基因转录。用在IE63蛋白中包含点突变的病毒感染导致几种病毒基因的转录降低。宿主细胞对该病毒或另一种小噬菌斑表型突变病毒的感染反应类似于感染完整的VZV，这表明该小噬菌斑表型是病毒基因表达不足而不是宿主细胞对病毒的反应所致。通过克隆两个不同的萤光素酶基因之间的1.5kb ORF62 / 63基因间区域来分析编码立即早期调节蛋白IE62和IE63的ORF62和ORF63的转录，该基因充当ORF62或ORF63表达的报告基因。将该报道基因盒插入病毒基因组中，以便可以在VZV感染期间监测ORF62和ORF63的转录，而不会影响病毒的生长。发现细胞转调节蛋白结合位点的突变可改变成纤维细胞中ORF62和ORF63报告基因之一或两者的荧光素酶活性。微阵列结果还表明，病毒感染改变了特定宿主细胞信号通路的调控，包括对NF-κB通路的抑制。该途径介导感染的炎症反应，被VZV诱导的IkappaBalpha水平稳定以及感染细胞中NF-kappaB蛋白的相关细胞质隔离所抑制。

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  • 作者

    Jones, Jeremy Orion.;

  • 作者单位

    Stanford University.;

  • 授予单位 Stanford University.;
  • 学科 Biology Microbiology.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 131 p.
  • 总页数 131
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 微生物学;
  • 关键词

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