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Activation of proinflammatory cytokine synthesis by variants of the paramyxovirus simian virus 5.

机译：副粘病毒猿猴病毒5的变体激活促炎细胞因子的合成5。

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摘要

Cytokines induced by virus infection can play an important role in pathogenesis, virus tropism and spread, and host immunity. Simian virus 5 (SV5) is unusual among paramyxoviruses since infection of epithelial cells results in minimal cytopathic effect and a poor activation of interferon (IFN) pathways. Gene microarray and timecourse experiments indicated that WT rSV5 was also a very poor inducer of proinflammatory cytokines, with the notable exception of moderate induction of RANTES at later times post-infection. By contrast, an engineered P/V mutant (rSV5-P/V-CPI-) and a naturally-occurring variant WF-PIV (Wake Forest - Parainfluenza Virus) were both potent activators of a number of cytokines, including IL-8, IL-6, and RANTES. The mechanism of RANTES induction by the two SV5 variants shared common properties, since RANTES secretion from infected cells had similar kinetics, depended on virus replication, correlated with increased RANTES promoter activation, and was reduced by inhibitors of MAPK and PI3K pathways. Based on previous work on rSV5-P/V-CPI-, we tested the hypothesis that the two SV5 variants activated cytokine secretion due to P/V mutations that accelerated gene expression. Surprisingly, in contrast to the accelerated viral gene expression of rSV5-P/V-CPI-, WF-PIV infection showed a delay in viral replication and infected cells did not show high level viral RNA and protein expression until ∼12--24 h pi. Sequence analysis of the WF-PIV 3' end genes revealed a number of mutations compared to WT rSV5. Chimeric viruses harboring the WF-PIV P/V or M genes in the context of the other rSV5 genes had growth properties similar to WT rSV5 but induced RANTES secretion to levels higher than that seen with WT rSV5, indicating a role for the WF-PIV P/V and M genes in RANTES induction. Furthermore, a cell line stably expressing WT SV5 V protein secreted reduced levels of RANTES following infection with rSV5-P/V-CPI-, but not following infection with WF-PIV. These data support a model in which the two SV5 variants have distinct molecular bases for the induction of cytokines---rSV5-P/V-CPI---is defective in V protein function while WF-PIV produces an inducer not normally seen during WT rSV5 infection.
机译：病毒感染诱导的细胞因子可以在发病机理，病毒嗜性和传播以及宿主免疫中发挥重要作用。猿猴病毒5（SV5）在副粘病毒中不常见，因为上皮细胞的感染导致最小的细胞病变作用和干扰素（IFN）途径的激活不良。基因芯片和时程实验表明，WT rSV5还是促炎性细胞因子的非常差的诱导剂，但在感染后的后期适度诱导RANTES是一个明显的例外。相比之下，工程改造的P / V突变体（rSV5-P / V-CPI-）和天然存在的变体WF-PIV（唤醒森林-副流感病毒）都是多种细胞因子（包括IL-8）的有效激活剂， IL-6和RANTES。这两个SV5变体诱导RANTES的机制具有共同的特性，因为感染细胞分泌的RANTES具有相似的动力学，取决于病毒复制，与RANTES启动子激活相关，并被MAPK和PI3K途径的抑制剂所降低。基于先前关于rSV5-P / V-CPI-的工作，我们测试了两个SV5变体由于加速基因表达的P / V突变而激活细胞因子分泌的假说。令人惊讶的是，与rSV5-P / V-CPI-的加速病毒基因表达相反，WF-PIV感染显示病毒复制延迟，并且受感染的细胞直到约12--24小时才显示出高水平的病毒RNA和蛋白质表达。 。 WF-PIV 3'末端基因的序列分析表明，与WT rSV5相比，存在许多突变。在其他rSV5基因的背景下具有WF-PIV P / V或M基因的嵌合病毒具有与WT rSV5相似的生长特性，但诱导RANTES分泌的水平高于WT rSV5所见水平，表明WF-PIV的作用RANTES诱导中的P / V和M基因。此外，稳定表达WT SV5 V蛋白的细胞系在感染rSV5-P / V-CPI-后分泌了降低的RANTES水平，但在WF-PIV感染后并未分泌。这些数据支持了一个模型，其中两个SV5变体具有不同的分子基础来诱导细胞因子-rSV5-P / V-CPI-的V蛋白功能存在缺陷，而WF-PIV产生的诱导物通常在WT rSV5感染。

著录项

  • 作者

    Young, Virginia Abigail.;

  • 作者单位

    Wake Forest University.;

  • 授予单位 Wake Forest University.;
  • 学科 Biology Microbiology.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 135 p.
  • 总页数 135
  • 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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