Deciphering molecular mechanisms of SARS-CoV-2 pathogenesis and drug repurposing through GRN motifs: a comprehensive systems biology study

Abstract

The world has recently been plagued by a new coronavirus infection called SARS-CoV-2. This virus may lead to severe acute respiratory syndrome followed by multiple organ failure. SARS-CoV-2 has approximately 80-90% genetic similarity to SARS-CoV. Given the limited omics data available for host response to the viruses (more limited data for SARS-CoV-2), we attempted to unveil the crucial molecular mechanisms underlying the SARS-CoV-2 pathogenesis by comparing its regulatory network motifs with SARS-CoV. We also attempted to identify the non-shared crucial molecules and their functions to predict the specific mechanisms for each infection and the processes responsible for their different manifestations. Deciphering the crucial shared and non-shared mechanisms at the molecular level and signaling pathways underlying both diseases may help shed light on their pathogenesis and pave the way for other new drug repurposing against COVID-19. We constructed the GRNs for host response to SARS-CoV and SARS-CoV-2 pathogens (in vitro) and identified the significant 3-node regulatory motifs by analyzing them topologically and functionally. We attempted to identify the shared and non-shared regulatory elements and signaling pathways between their host responses. Interestingly, our findings indicated that NFKB1, JUN, STAT1, FOS, KLF4, and EGR1 were the critical shared TFs between motif-related subnetworks in both SARS and COVID-1, which are considered genes with specific functions in the immune response. Enrichment analysis revealed that the NOD-like receptor signaling, TNF signaling, and influenza A pathway were among the first significant pathways shared between SARS and COVID-19 up-regulated DEGs networks, and the term "metabolic pathways" (hsa01100) among the down-regulated DEGs networks. WEE1, PMAIP1, and TSC22D2 were identified as the top three hubs specific to SARS. However, MYPN, SPRY4, and APOL6 were the tops specific to COVID-19 in vitro. The term "Complement and coagulation cascades" pathway was identified as the first top non-shared pathway for COVID-19 and the MAPK signaling pathway for SARS. We used the identified crucial DEGs to construct a drug-gene interaction network to propose some drug candidates. Zinc chloride, Fostamatinib, Copper, Tirofiban, Tretinoin, and Levocarnitine were the six drugs with higher scores in our drug-gene network analysis.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-023-03518-x.

Keywords: COVID-19; DEGs; Host response; Regulatory network motifs; SARS.

Fig. 1

This workflow represents the graphical overview of the study

Fig. 2

The intersection among motif-related subnetworks of SARS up-regulated DEGs network. The V-shape nodes show only TFs; circle nodes represent miRNAs; diamond nodes depict only genes. The regulatory nodes modulate the shared DEGs between all five significant motif-related subnetworks of the SARS up-regulated DEGs network. All motifs are represented by their identification motif number in the FANMOD software encyclopedia. Z-scores (> 2) and P values (< 0.05) are reported for each motif

Fig. 3

The intersection among motif-related subnetworks of COVID-19 up-regulated DEGs network. The V-shape nodes show only TFs; circle nodes represent miRNAs; diamond nodes depict TF/Genes (Dual role). The regulatory nodes modulate the shared DEGs between all three (three motif IDs) significant motif-related subnetworks of the COVID-19 up-regulated DEGs network. All motifs are represented by their identification motif number in the FANMOD software encyclopedia. Z-scores (> 2) and P values (< 0.05) are reported for each motif

Fig. 4

The drug–gene interaction network. Green ovals show the crucial identified Genes, and diamonds depict our repurposed medications. The medicines previously registered for clinical trials against COVID-19 are distinct, using violet color

Fig. 5

The integrative diagram summarizes the crucial molecules and mechanisms