Variants of the paramyxovirus Simian virus 5 with accelerated or delayed viral gene expression activate proinflammatory cytokine synthesis.
Variants of the paramyxovirus Simian virus 5 with accelerated or delayed viral gene expression activate proinflammatory cytokine synthesis.
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副粘病毒猴病毒 5 的变种具有加速或延迟病毒基因表达，可激活促炎细胞因子的合成。
DOI：
10.1016/j.virol.2006.01.006
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发表时间：
2006
期刊：
影响因子：
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通讯作者：
Parks,GriffithD
中科院分区：
文献类型：
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作者：
Young,VirginiaA;Dillon,PatrickJ;Parks,GriffithD
我们以前的研究结果表明，副流感病毒SV 5是促炎细胞因子白细胞介素-8（IL-8）和巨噬细胞趋化蛋白1（MCP-1）的不良诱导剂。相比之下，工程改造的P/V突变体rSV 5-P/V-CPI−和天然存在的变体WF-PIV（维克森林副流感病毒）都是IL-8和MCP-1的有效激活剂。在本研究中，我们解决了为什么rSV 5-WT相对于两种SV 5变体是如此差的宿主细胞因子应答诱导剂的问题，并且我们使用CC趋化因子RANTES作为宿主应答的量度。时程实验显示，在用P/V-CPI−突变体和WF-PIV感染人A549肺上皮细胞后，IL-6和RANTES的分泌水平较高。相比之下，SV 5-WT诱导非常低的细胞因子应答，显著的例外是RANTES的中度诱导。两种SV 5变体的RANTES诱导机制具有共同的特性，因为感染细胞的RANTES分泌具有相似的动力学，依赖于病毒复制，与RANTES mRNA水平增加和启动子激活相关，并且通过p38 MAPK、ERK和PI 3 K通路的抑制剂降低。尽管RANTES诱导的机制相似，但两种SV 5变体在生长和基因表达动力学方面存在显著差异。与加速病毒基因表达的P/V突变体rSV 5-P/V-CPI-相比，WF-PIV感染显示病毒复制延迟时间延长，并且感染细胞直到12-24 hpi才显示高水平的病毒RNA和蛋白质表达。序列分析显示，与rSV 5-WT相比，WF-PIV的N、P、V和M基因分别相差3、8、5和10个氨基酸。在其他rSV 5基因的背景下携带WF-PIV P/V或M基因的嵌合病毒具有与rSV 5-WT相似的生长特性，但具有与真正WF-PIV病毒相似的RANTES诱导表型。我们的数据表明，P/V和M基因产物作为决定因素的RANTES诱导SV 5感染的作用。
Our previous results have shown that the parainfluenza virus SV5 is a poor inducer of proinflammatory cytokines interleukin-8 (IL-8) and macrophage chemoattractant protein 1 (MCP-1). By contrast, an engineered P/V mutant rSV5-P/V-CPI− and a naturally-occurring variant WF-PIV (Wake Forest–Parainfluenza Virus) are both potent activators of IL-8 and MCP-1. In the present study, we addressed the question of why rSV5-WT is such a poor inducer of host cytokine responses relative to the two SV5 variants, and we used the CC chemokine RANTES as a measure of host responses. Time course experiments showed high-level secretion of IL-6 and RANTES following infections of human A549 lung epithelial cells with the P/V-CPI− mutant and WF-PIV. By contrast, SV5-WT induced very low cytokine responses, with the notable exception of moderate induction of 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 mRNA levels and promoter activation, and was reduced by inhibitors of the p38 MAPK, ERK, and PI3K pathways. Despite the similar mechanisms of RANTES induction, the two SV5 variants differed dramatically in their growth and gene expression kinetics. By comparison to the P/V mutant rSV5-P/V-CPI− which has accelerated viral gene expression, WF-PIV infection showed a prolonged delay in viral replication, and infected cells did not show high-level viral RNA and protein expression until ∼12–24 hpi. Sequence analysis revealed that the N, P, V, and M genes from WF-PIV differed by 3, 8, 5, and 10 amino acids compared to rSV5-WT, respectively. Chimeric viruses harboring the WF-PIV P/V or M genes in the context of the other rSV5 genes had growth properties similar to rSV5-WT but had a RANTES-inducing phenotype similar to that of the bone fide WF-PIV virus. Our data indicate a role for both the P/V and the M gene products as determinants of RANTES induction in response to SV5 infection.