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. 2015 May 26:5:9912.
doi: 10.1038/srep09912.

Systematic Genome-wide Screening and Prediction of microRNAs in EBOV During the 2014 Ebolavirus Outbreak

Yue Teng  1 , Yuzhuo Wang  2 , Xianglilan Zhang  1 , Wenli Liu  1 , Hang Fan  1 , Hongwu Yao  1 , Baihan Lin  3 , Ping Zhu  2 , Wenjun Yuan  4 , Yigang Tong  1 , Wuchun Cao  1
Affiliations

Systematic Genome-wide Screening and Prediction of microRNAs in EBOV During the 2014 Ebolavirus Outbreak

Yue Teng et al. Sci Rep. .

Abstract

Recently, several thousand people have been killed by the Ebolavirus disease (EVD) in West Africa, yet no current antiviral medications and treatments are available. Systematic investigation of ebolavirus whole genomes during the 2014 outbreak may shed light on the underlying mechanisms of EVD development. Here, using the genome-wide screening in ebolavirus genome sequences, we predicted four putative viral microRNA precursors (pre-miRNAs) and seven putative mature microRNAs (miRNAs). Combing bioinformatics analysis and prediction of the potential ebolavirus miRNA target genes, we suggest that two ebolavirus coding possible miRNAs may be silence and down-regulate the target genes NFKBIE and RIPK1, which are the central mediator of the pathways related with host cell defense mechanism. Additionally, the ebolavirus exploits the miRNAs to inhibit the NF-kB and TNF factors to evade the host defense mechanisms that limit replication by killing infected cells, or to conversely trigger apoptosis as a mechanism to increase virus spreading. This is the first study to use the genome-wide scanning to predict microRNAs in the 2014 outbreak EVD and then to apply systematic bioinformatics to analyze their target genes. We revealed a potential mechanism of miRNAs in ebolavirus infection and possible therapeutic targets for Ebola viral infection treatment.

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Figures

Figure 1
Figure 1
The 102 complete genome sequences alignment of the 2014 outbreak EBOV. (A) Full alignment map of all 102 EBOV complete genomes. (B) Locations and putative target sites of the four real miRNA precursor candidates.
Figure 2
Figure 2
Workflow of the 2014 outbreak EBOV-encoded miRNA prediction. The MiPred algorithm was used to identify genuine pre-miRNAs, and the MatureBayes tool was used to predict the mature miRNA sequences.
Figure 3
Figure 3
Predicted hairpin structures of potential EBOV pre-miRNAs. (A) The primary structures of the four EBOV pre-miRNAs. (B) The secondary structures of the four EBOV pre-miRNAs. (C) The tertiary structures of the four EBOV pre-miRNAs.
Figure 4
Figure 4
Bioinformatic analysis of target gene prediction and related signaling pathways of the potential mature miRNAs in EBOV. The predicted target gene of potential mature EBOV miRNAs were classified by the GO and DAVID databases based on biological process (A), molecular function (B) and cellular compartment (C). (D) The pathway enrichment analysis of candidate genes. Top enriched pathways are listed (p value < 0.01). (E) The gene regulation network analysis of the potential target genes. (F) The detail information of target genes of miRNA EBV-miR-T3-5p, EBV-miR-T2-3p, EBV-miR-T2-3p and EBV-miR-T2-5p.
Figure 5
Figure 5
Signaling pathway analysis of the potential mature EBOV miRNA target genes. (A) The associated genes of Edema, □-kappaB kinase/ NF-kappaB cascade and replication of virus. (B) The associated genes of cell death of kidney cell lines, failure of heart, congestive heart failure, hepatorenal syndrome and cell death of cardiomyocytes. (B) TNF signaling pathway. (C) NF-κB signaling pathway. (D) Detail information of target gene NFKBIE. (E) Detail information of target gene RIPK1.
Figure 6
Figure 6
Transfection efficiency of EBOV-miRNA mimics and effect of the EBOV-miRNA mimics on the expression of target genes in Hela cells. (A) Transfection efficiency 24 h post-transfection in Hela cells as percentage of fluorescent dye labeled miRNA positive cells. (B) Relative expression levels of NFKIBIE, RIPK1, HDAC5 and JARID2, which were regulated by EBOV-miRNA mimics miR-T1-5p, miR-T2-3p and miR-T3-5p, respectively. (C) Relative expression levels of NFKIBIE and RIPK1, which were regulated by six EBOV-miRNA mimics and their mixed miRNA (MIX miRNA). *: P < 0.05, **: P < 0.01, ***: P < 0.001. Label “NC” means negative control.
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