Combined miRNA and mRNA signature identifies key molecular players and pathways involved in chikungunya virus infection in human cells.
Combined miRNA and mRNA signature identifies key molecular players and pathways involved in chikungunya virus infection in human cells.
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DOI：
10.1371/journal.pone.0079886
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kulshreshtha R
中科院分区：
文献类型：
--
作者：
Saxena T;Tandon B;Sharma S;Chameettachal S;Ray P;Ray AR;Kulshreshtha R
自发现基孔肯雅热以来，由一种病毒（CHIKV）引起的基孔肯雅热肆虐了非洲和东南亚的大部分地区。尽管仅在印度就有100多万例报告病例，而且该病的严重程度处于慢性期，但对该病的发病机制和宿主反应的明确认识仍然难以捉摸。本研究利用微阵列技术和定量PCR方法，在人细胞系感染模型HEK293T中建立了宿主对CHIKV感染反应的完整miRNA、snoRNA和mRNA特征。结果在人原代细胞（真皮成纤维细胞）中得到进一步验证。miRNA表达谱显示152种miRNA在CHIKV感染后受到调控。在HCV、HPV和hiv病毒中发现了一个有趣的miRNA特征重叠。通过qRT-PCR进一步验证的微阵列数据显示，miR-744、miR-638、miR-503等顶级上调miRNAs均被诱导。值得注意的是，我们发现了属于C/D集群的snorna的诱导，包括U3， U44， U76和U78 snorna的近亲。基因在3条主要途径上存在差异表达；TGF-β，内吞作用和细胞周期途径。qRT-PCR数据证实了TGF-β （SMAD6、JUN、skill）和胞吞途径（CXCR4、HSPA8、ADRB1）基因的强诱导，而细胞周期基因（CDC27、CDC23）的下调。有趣的是，TGF-β抑制剂SB-431542的使用增加了CHIKV介导的细胞死亡。总的来说，本研究旨在提供宿主对CHIKV感染反应的第一个完整转录组特征，以帮助鉴定可能的生物标志物和治疗靶点。
Since its discovery, Chikungunya fever caused by a virus (CHIKV) has ravaged most of Africa and Southeast Asia. Despite there being more than a million reported cases in India alone and the seriousness of the disease in the chronic phase, a clear understanding of the disease pathogenesis and host response remains elusive. Here, we use microarray technology and quantitative PCR method to establish the complete miRNA, snoRNA and mRNA signature of host response upon CHIKV infection in human cell line infection model, HEK293T. The results were further validated in human primary cells (dermal fibroblasts). miRNA expression profiling revealed regulation of 152 miRNAs post CHIKV infection. An interesting overlap in miRNA signature was seen majorly with HCV, HPV and HIV1 virus. The microarray data further validated by qRT-PCR revealed induction of miR-744, miR-638, miR-503 and others among the top upregulated miRNAs. Notably, we found induction of snoRNAs belonging to C/D cluster including close paralogs of U3, U44, U76 and U78 snoRNAs. Genes were found to be differentially expressed along 3 major pathways; TGF-β, endocytosis and the cell cycle pathways. qRT-PCR data confirmed strong induction of TGF-β (SMAD6, JUN, SKIL) and endocytosis pathway (CXCR4, HSPA8, ADRB1) genes while downregulation of cell cycle genes (CDC27 and CDC23). Interestingly, use of TGF-β inhibitor, SB-431542, increased CHIKV mediated cell death. Overall, this study aims at providing the first complete transcriptome signature of host response upon CHIKV infection to aid identification of possible biomarkers and therapeutic targets.
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