Unraveling the molecular crosstalk between Atherosclerosis and COVID-19 comorbidity

Abstract

Background: Corona virus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has created ruckus throughout the world. Growing epidemiological studies have depicted atherosclerosis as a comorbid factor of COVID-19. Though both these diseases are triggered via inflammatory rage that leads to injury of healthy tissues, the molecular linkage between them and their co-influence in causing fatality is not yet understood.

Methods: We have retrieved the data of differentially expressed genes (DEGs) for both atherosclerosis and COVID-19 from publicly available microarray and RNA-Seq datasets. We then reconstructed the protein-protein interaction networks (PPIN) for these diseases from protein-protein interaction data of corresponding DEGs. Using RegNetwork and TRRUST, we mapped the transcription factors (TFs) in atherosclerosis and their targets (TGs) in COVID-19 PPIN.

Results: From the atherosclerotic PPIN, we have identified 6 hubs (TLR2, TLR4, EGFR, SPI1, MYD88 and IRF8) as differentially expressed TFs that might control the expression of their 17 targets in COVID-19 PPIN. The important target proteins include IL1B, CCL5, ITGAM, IFIT3, CXCL1, CXCL2, CXCL3 and CXCL8. Consequent functional enrichment analysis of these TGs have depicted inflammatory responses to be overrepresented among the gene sets.

Conclusion: Finally, analyzing the DEGs in cardiomyocytes infected with SARS-CoV-2, we have concluded that MYD88 is a crucial linker of atherosclerosis and COVID-19, the co-existence of which lead to fatal outcomes. Anti-inflammatory therapy targeting MYD88 could be a potent strategy for combating this comorbidity.

Keywords: Atherosclerosis; COVID-19; Differentially expressed genes; Protein-protein interaction network; SARS-CoV-2; Transcription factors.

Graphical abstract

Fig. 1

DEGs in atherosclerosis, reconstruction of atherosclerosis PPIN and identification of hub genes. (A.) Venn diagram representing DEGs derived from the three atherosclerotic studies. (B.) Heatmap comparing the expression of DEGs for the three atherosclerotic studies. (C.) PPIN for atherosclerosis. The red nodes represent DEGs in the PPIN and other interactors of the network are cyan colored. (D.) Sub network of hub genes from main PPIN for atherosclerosis with nodes having variable color depth to represent the degree centrality of hub genes.

Fig. 2

Functional and pathway enrichment analysis for hub genes in atherosclerosis PPIN. (A.) GO-biological process enrichment of hub genes. The bar plot represents no. of genes enriched for each function and the color gradient represents significance value (FDR <0.05). (B.) GO-molecular function enrichment of hub genes. The bar plot represents no. of genes enriched for each function and the color gradient represents its significance value (FDR <0.05). (C.) GO- cellular component enrichment of hub genes. The bar plot represents no. of genes enriched for each function and the color gradient represents its significance value (FDR <0.05). (D.) KEGG pathway enrichment of hub genes. The bar plot represents no. of genes enriched for each function and the color gradient represents its significance value (adj. P value < 0.05).

Fig. 3

DEGs in COVID-19 and the reconstruction of COVID-19 PPIN. (A.) Venn diagram representing DEGs derived from the two COVID-19 studies. (B.) Heatmap comparing the expression of DEGs for the two COVID-19 studies. (C.) PPIN for COVID-19. The red nodes represent DEGs in the PPIN and other interactors of the network are blue colored.

Fig. 4

Functional and pathway enrichment analysis of atherosclerotic DETFs targeted genes in COVID-19 network. (A.) GO-biological process enrichment of TGs in COVID-19 network for atherosclerotic DETFs. The bar plot represents no. of genes enriched for each function and the color gradient represents significance value (FDR <0.05). (B.) GO-molecular function enrichment of TGs in COVID-19 network for atherosclerotic hub DETFs. The bar plot represents no. of genes enriched for each function and the color gradient represents its significance value (FDR <0.05). (C.) GO- cellular component enrichment of TGs in COVID-19 network for atherosclerotic hub DETFs. The bar plot represents the no. of genes enriched for each function and the color gradient represents its significance value (FDR <0.05). (D.) KEGG pathway enrichment of TGs in COVID-19 network for atherosclerotic hub DETFs. The bar plot represents the no. of genes enriched for each function and the color gradient represents its significance value (adj. P value < 0.05).

Fig. 5

Expression and network analysis of DETF- TG interactions. (A.) Volcano plot representing the expression of genes in cardiomyocyte infected with SARS-CoV-2. Genes are considered as significantly expressed only if adj. P value < 0.05 and |log₂FC|>1.0. The green dots represent significantly upregulated genes, red dots represent significantly downregulated genes and grey dots represent non-significant DEGs. (B.) TF-TG interaction in cardiomyocytes infected with SARS-CoV-2.

Fig. 6

Overview of the major immunological signaling events linking atherosclerosis and COVID-19 in cardiomyocytes. In response to both dying cells and SARS-CoV-2, TLR4 and TLR2 might be initiating inflammatory response by activating MyD88. MyD88 might be either activating NF-κB pathway or by itself initiating release of pro-inflammatory cytokines – CXCL1, CXCL2, CXCL3, CXCL8 and IL-1β which leads to cytokine storm in cardiac tissue.