Identification of Transcription Factors Regulating SARS-CoV-2 Tropism Factor Expression by Inferring Cell-Type-Specific Transcriptional Regulatory Networks in Human Lungs

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that caused the coronavirus disease 2019 (COVID-19) pandemic. Though previous studies have suggested that SARS-CoV-2 cellular tropism depends on the host-cell-expressed proteins, whether transcriptional regulation controls SARS-CoV-2 tropism factors in human lung cells remains unclear. In this study, we used computational approaches to identify transcription factors (TFs) regulating SARS-CoV-2 tropism for different types of lung cells. We constructed transcriptional regulatory networks (TRNs) controlling SARS-CoV-2 tropism factors for healthy donors and COVID-19 patients using lung single-cell RNA-sequencing (scRNA-seq) data. Through differential network analysis, we found that the altered regulatory role of TFs in the same cell types of healthy and SARS-CoV-2-infected networks may be partially responsible for differential tropism factor expression. In addition, we identified the TFs with high centralities from each cell type and proposed currently available drugs that target these TFs as potential candidates for the treatment of SARS-CoV-2 infection. Altogether, our work provides valuable cell-type-specific TRN models for understanding the transcriptional regulation and gene expression of SARS-CoV-2 tropism factors.