The C Proteins of Human Parainfluenza Virus Type 1 (HPIV1) Control the Transcription of a Broad Array of Cellular Genes That Would Otherwise Respond to HPIV1 Infection
The C Proteins of Human Parainfluenza Virus Type 1 (HPIV1) Control the Transcription of a Broad Array of Cellular Genes That Would Otherwise Respond to HPIV1 Infection
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DOI：
10.1128/jvi.01373-08
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发表时间：
2009-02-15
影响因子：
5.4
通讯作者：
Schmidt, Alexander C.
中科院分区：
文献类型：
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作者：
Boonyaratanakornkit, Jim B.;Bartlett, Emmalene J.;Schmidt, Alexander C.
人副流感病毒1型（HPIV 1）是儿童呼吸道重要病原体，也是病毒性哮吼最常见的病因。我们进行了基于基因表达动力学的微阵列分析，以研究野生型（wt）HPIV 1感染如何改变人类呼吸道上皮细胞中的基因表达，以及β干扰素在这种反应中发挥了什么作用。我们类似地评价了HPIV 1-P（C-），一种高度减毒的诱导凋亡的病毒，不表达四种C蛋白中的任何一种，以及HPIV 1-C-F170 S，一种减毒程度较低的突变体，其在C中含有一个单点突变，并且与wt HPIV 1一样，不能有效地诱导凋亡，以检查C蛋白在控制宿主基因表达中的作用。我们还使用这些数据来研究两个C突变体之间的表型差异是否可以在转录水平上解释。HPIV 1的C蛋白的突变或缺失允许超过2，000个细胞基因的激活，否则这些基因将被HPIV 1感染抑制。因此，C蛋白深刻地抑制人呼吸道细胞对HPIV 1感染的反应。鉴定了HPIV 1C蛋白靶向的细胞途径，并使用生物信息学分析了其转录控制。IRF和NF-κ B B的转录因子结合位点在一些C蛋白靶向途径中过度表达，但其他途径由不太知名的因子（如叉头转录因子FOXD 1）主导。令人惊讶的是，宿主对P（C-）和C-F170 S突变体的反应非常相似，并且仅观察到胱天蛋白酶3和TRAIL受体2的表达动力学的细微差异。因此，宿主细胞转录的变化并不反映这两种病毒之间观察到的显著表型差异。
Human parainfluenza virus type 1 (HPIV1) is an important respiratory pathogen in children and the most common cause of viral croup. We performed a microarray-based analysis of gene expression kinetics to examine how wild-type (wt) HPIV1 infection altered gene expression in human respiratory epithelial cells and what role beta interferon played in this response. We similarly evaluated HPIV1-P(C-), a highly attenuated and apoptosis-inducing virus that does not express any of the four C proteins, and HPIV1-C-F170S, a less attenuated mutant that contains a single point mutation in C and, like wt HPIV1, does not efficiently induce apoptosis, to examine the role of the C proteins in controlling host gene expression. We also used these data to investigate whether the phenotypic differences between the two C mutants could be explained at the transcriptional level. Mutation or deletion of the C proteins of HPIV1 permitted the activation of over 2,000 cellular genes that otherwise would be repressed by HPIV1 infection. Thus, the C proteins profoundly suppress the response of human respiratory cells to HPIV1 infection. Cellular pathways targeted by the HPIV1 C proteins were identified and their transcriptional control was analyzed using bioinformatics. Transcription factor binding sites for IRF and NF-kappa B were overrepresented in some of the C protein-targeted pathways, but other pathways were dominated by less-known factors, such as forkhead transcription factor FOXD1. Surprisingly, the host responses to the P(C-) and C-F170S mutants were very similar, and only subtle differences in the expression kinetics of caspase 3 and TRAIL receptor 2 were observed. Thus, changes in host cell transcription did not reflect the striking phenotypic differences observed between these two viruses.