Gene Network Inference from Single-Cell Omics Data and Domain Knowledge for Constructing COVID-19-Specific ICAM1-Associated Pathways

ICAM-1 is critical for interactions between cells. Previous studies have suggested that ICAM-1 triggers cell-to-cell transmission of HIV-1 or HTLV-1. SARS-CoV-2 shares several features with these viruses in interactions between cells, and SARS-CoV-2 cell-to-cell transmission is associated with COVID-19 severity. However, ICAM-1 and its associated pathways are not identified as essential factors in interactions between cells in COVID-19. For example, the current COVID-19 Disease Map has no entry for those pathways. Therefore, discovering unknown ICAM-1 pathways will be indispensable for clarifying the mechanism of COVID-19. This study builds ICAM1-associated pathways by gene network inference from single-cell omics data and multiple knowledge bases. First, data analyses extracted coexpressed genes with significant differences in expression levels with spurious correlations removed. Second, knowledge bases validate models. Finally, mapping the models onto existing pathways identifies new ICAM1-associated pathways. These pathways indicate that (1) upstream pathways include proteins in noncanonical NF-kappaB pathway and that (2) downstream pathways contain integrins and cytoskeleton or motor proteins for cell transformation. In this way, data-driven and knowledge-based approaches are integrated into gene network inference for ICAM1-associated pathway construction. The results can contribute to repairing and completing the COVID-19 Disease Map, thereby improving our understanding of the mechanisms of COVID-19.