Deciphering the molecular pathogenesis behind neurological manifestations of SARS-CoV-2 and drug repurposing, a systems biology approach

Abstract

Introduction: As the COVID-19 pandemic spreads worldwide, reports about the neurological complications of SARS-CoV-2 are excessively increasing. However, there is still insufficient high-throughput data on neuronal cells infected with SARS-CoV-2 to help predict its neural pathogenesis. HCoV-OC43 is another member of the beta coronavirus family that has confirmed neuro-invasive effects and has available neural omics data. This study predicts the critical genes, biological processes, and pathways mediating in SARS-CoV-2 neurological manifestations using a systems biology approach.Method: We retrieved raw data related to SARS-CoV-2 and HCoV-OC43 infections from gene expression omnibus datasets (GSE147507 and GSE13879 respectively). We constructed gene regulatory networks for both infections, detected significant regulatory motifs by FANMOD software, and created their subnetworks. We also constructed PPI networks and identified the MCODE clusters. In the intersection of merged subnetworks of two viruses, the most critical genes were verified in GRN & PPI networks. We drug-repurposed for the selected target genes and performed the functional enrichment analysis using DAVID and String databases.Results: Some of the top KEGG pathway results included NF-kappa B, Toll-like receptor, NOD-like receptor, MAPK, and Neurotrophin signaling pathways. The most essential identified genes included IL6, TNF, HOXA5, POU2F2, ITGB3, STAT1, YY1, E2F6, ESR1, FOXO3, FOXO1, MEF2A, ATF3, ATF4, DDIT3, TCF4, BCL2L2, and BMP4. These genes were also involved in mechanisms of other viral infections of the nervous system. This study repurposes nine medicines with effects on COVID-19 neurological complications. Some of the repurposed drugs were previously registered in clinical trials for COVID-19 treatment.Conclusion: We recommended some identified crucial genes and medications to investigate further their potential role in treating COVID-19 neurological complications.