Abstract
Epstein-Barr Virus (EBV), also called as human herpesvirus 4 (HHV-4), is prevalent in all human populations. EBV mainly infects human B lymphocytes and epithelial cells, so it is associated with the various malignancies about them. In this study, we want to construct the interspecies networks to investigate the cross-talk molecular mechanisms between human B cells and EBV at the first infection stage (0~24 hours) and at the second infection stage (8~72 hours) during the EBV infection, respectively. We first construct a candidate genome-wide interspecies genetic- and epigenetic- network (candidate GIGEN) through big databases mining. Then we prune the false positives in the candidate GIGEN to obtain the real GIGENs at the first and second infection stage in the lytic phase by their corresponding NGS data through the dynamic interaction models, the system identification approach, and the system order detection method. The GIGEN consists of protein-protein interaction networks (PPINs), gene/miRNA/lncRNA regulation networks (GRNs), host-virus cross-talk networks. Since the GIGENs are still very complex. In order to gain an insight into the cross-talk molecular mechanisms of the EBV infection, the core GIGENs including host-virus core networks (HVCNs) and host-virus core pathways (HVCPs) are extracted from GIGENs by the principal network projection (PNP) method. On the basis of these identified results, we found that EBV can exploit viral proteins and miRNAs to inhibit the activities of the epigenetics-associated human proteins or genes at first, and then may hijack the functions of the epigenetic regulations to make human immune responses dysregulated. Moreover, viral proteins EBNA2 and Zta play the primary role in the initiation of EBV lytic phase and could be considered as the potential drug targets. EBNA2 is efficient in upregulating genes involving in the infected cell proliferation and survival to evade human immune attacks. Besides, the immediate-early lytic gene product, Zta, is a transcription factor able to induce the entire program of the EBV lytic gene expression. Additionally, EBV membrane protein LMP2B works in cooperation with LMP1 via viral BLLF2 to enhance the activity of human B cells and facilitate the production and transportation of the viral particles, and EBV nuclear antigen EBNA1 is crucial for EBV to reproduce via anti-apoptosis; thus, these viral proteins could be suggested as the potential drug targets. Eventually, we proposed the multi-molecule drugs composed of Thymoquinone (TQ), Valpromide (VPM), and Zebularine (Zeb) to target the drug targets for the therapeutic intervention as the inhibitors of the EBV-associated malignancies.