Integrative Systemic Analysis of the Molecular Network Associated with Neuroimmune Dysregulation Induced by Viral Hepatitis

Hepatitis viruses have been associated with various neurological conditions such as cerebrovascular events, encephalomyelitis, cognitive impairment, and psychiatric disorders including anxiety and fatigue. However, the neuroimmune networks and mechanisms triggered by viral hepatitis infections have not been fully explored. To gain insights, we conducted an integrated analysis of molecular networks induced by different hepatitis viruses (HBV, HCV, and HDV), known for their oncogenic potential. We performed differential expression analysis, with batch effect correction using the Combat package, followed by a meta-analysis on 1125 transcriptomes comprising microarray and RNA sequencing data from infected patients (445 liver samples, 122 PBMC) compared to control transcriptomes (446 liver samples, 112 PBMC). Our findings revealed significantly regulated meta-DEGs as follows: 645 (HBV/Liver), 201 (HCV/Liver), 1478 (HDV/Liver), 129 (HBV/PBMC), 123 (HCV/PBMC); and negatively regulated: 223 (HBV/Liver), 43 (HCV/Liver), 1327 (HDV/Liver), 42 (HBV/PBMC), and 87 (HCV/PBMC). Enrichment analysis using these meta-DEGs showed shared biological processes, with positively regulated genes mainly associated with immune responses such as interferon type II (CCL19, CCL20, HLA-DPA1), inflammatory response (CXL2, IL6, CD14, AGTR1), and cell cycle response (TIMP1, OSMR, RAB25, AREG). Conversely, negatively regulated meta-DEGs enriched various biological processes including neuroinflammatory response (e.g., IL6, IL1B, IFG1), dendritic cell migration (e.g., CXCR1, CXR2, CCR1), and positive regulation of erk1 and erk2 cascade (TEK, RAMP3, FGA). Network analysis revealed a strong interconnection between various neuroimmune pathways. Overall, this study unveils a previously unrecognized neuroimmune network involved in oncogenic hepatitis development, warranting further investigation into its association with disease severity.