Identification of Stage-Specific Differentially Expressed Genes and Network Meta-Analysis Reveals Potential Molecular Signatures in Chronic Hepatitis E Virus Infection

Abstract

Abstract Background Hepatitis E virus (HEV) is the major pathogen responsible for chronic hepatitis infection (CHE) in solid organ transplant recipients. As CHE seems to be dependent on patient’s immunological status, in this context, a comprehensive assessment of gene-, pathway-, and network-level interaction was accomplished to identify key regulators in CHE. To our knowledge, this study conducted novel analysis on the NCBI-GEO obtained mRNA expression profile comprising all three HEV infection stages, i.e., mild, moderate and severe. Methods The patients with CHE were separated into 3 groups according to the time of HEV clearance (early, late, or no HEV clearance at the time of analysis). Gene expression analysis was applied on microarray profile dataset, consisting of control samples (kidney transplant recipients without HEV) and infected samples (kidney transplant recipients with HEV), to unveil the differentially expressed genes (DEGs). Interrelationship among DEGs was studied to identify the overlapping DEGs, which were utilized for the construction of the protein-protein interaction (PPI) network. Additionally, the significant modules were identified form the PPI network. Gene term and pathway enrichment analyses were employed on the identified DEGs. Subsequently, the identified hub gene-associated miRNAs were undertaken for enrichment analysis. Results Our analysis revealed a total of 69, 157, and 411 specific DEGs which included 34 upregulated and 35 downregulated genes, 138 upregulated and 19 downregulated genes, and 326 upregulated and 85 downregulated genes for mild, moderate, and severe CHE respectively. Interestingly, we found upregulated expression levels of 8 genes BATF2, OASL, IFI44L, IFIT3, RSAD2, IFIT1, RASGRP3 and IFI27, which shows their association with persistent HEV infection. Of these genes, 6 (OASL, IFI27, IFIT1, IFIT3, RSAD2 and IFI44L) made into the PPI network and were common at each stage, thus, could serve as important area of interest for further research. Enrichment analysis showed DEGs association with binding and catalytic activities, viral replication and interferon signaling pathways. Furthermore, we identified key gene associated-miRNAs (miR-129-2-3p, miR-130a-3p, miR-138-5p, miR-212-3p, miR-221-3p, miR-27b-3p and miR-29c-3p). Conclusions The current study might provide insights into these identified key genes and pathways which could be targeted to offer better interventions for CHE in future biological research.