key: cord-0721633-mdy2zjcl authors: Das, Deepyaman; Podder, Soumita title: Unraveling the molecular crosstalk between Atherosclerosis and COVID-19 comorbidity date: 2021-05-01 journal: Comput Biol Med DOI: 10.1016/j.compbiomed.2021.104459 sha: 9f181e9f307a70da327a8fe37a41d2d31f424573 doc_id: 721633 cord_uid: mdy2zjcl 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 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. Syndrome Coronavirus -2 (SARS-CoV-2) has created ruckus throughout the world. Growing 29 epidemiological studies have depicted atherosclerosis as a comorbid factor of COVID-19. 30 Though both these diseases are triggered via inflammatory rage that leads to injury of healthy 31 tissues, the molecular linkage between them and their co-influence in causing fatality is not 32 understood. 33 Methods -We have retrieved the data of differentially expressed genes (DEGs) for both 34 atherosclerosis and COVID-19 from publicly available microarray and RNA-Seq datasets. We 35 then reconstructed the protein-protein interaction networks (PPIN) for these diseases from 36 protein-protein interaction data of corresponding DEGs. Using RegNetwork and TRRUST, 37 we mapped the transcription factors (TFs) in atherosclerosis and their targets (TGs) in 38 COVID-19 PPIN. Conclusion -Finally, analyzing the DEGs in cardiomyocytes infected with SARS-CoV-2, we 46 have concluded that MYD88 is a crucial linker of atherosclerosis and COVID-19, the co- 47 existence of which lead to fatal outcomes. Anti-inflammatory therapy targeting MYD88 could 48 be a potent strategy for combating this comorbidity. 69 inflammation mediated injury to the alveolar cells caused by cytokine release has been 70 popularly termed as "cytokine storm" [3] . 71 Concurrently, several reports from the epicenter of COVID-19 i.e., Wuhan, China had stated 72 that patients with cardiovascular disease (CVD) have greater risk of COVID-19 mediated 73 implications [5] [6] [7] [8] . Several studies from different countries have documented that mortality 74 rate of COVID-19 patients having pre-existing cardiovascular disease varies between 11%-75 19% [9-12]. It was found that 50% of the patients with coronary artery calcifications (CAC+) 76 were severely affected by COVID-19, whereas only 17% of the patients with no coronary 77 calcifications were severely affected [13] . Moreover, a possible correlation between COVID-78 19 and atherosclerosis has been shown to amplify the immune response of the body and 79 instigating acute coronary syndromes [14] . It has also been proposed that atherosclerosis is 80 the most common form of cardiovascular disease (CVD) which is characterized by the 81 buildup of lipid laden macrophages (foam cells) within walls of large arteries like coronary 82 J o u r n a l P r e -p r o o f 4 artery [15] . Accumulation of apoB-LPs, that are formed from LDL, attracts monocytes which 83 orchestrate the early inflammatory response against the congregated apoB-LPs in the arterial 84 intima [16] . The activated endothelial (EC) cells of the arterial wall secrete chemokines such 85 as CCL5 and CXCL1 which facilitates entry of monocytes in the intimal space [17, 18] . 86 Monocytes, after their conversion to foam cells, secrete various chemokines like IL-6, IL-12 87 and TNF-α to mediate inflammatory response in this disease [16] . In addition to that, ACE2, a 88 negative regulator of RAS (renin-angiotensin system) has been proved to play an important 89 role in progression of atherosclerosis since it converts angiotensin-II (Ang-II) into the 90 vasodilator DEGs are found to be common in three datasets ( Figure 1A (Table 1) . We identified six hub 231 genes, namely -TLR2, TLR4, EGFR, SPI1, MYD88 and IRF8 as TFs. All these TFs are 232 significantly differentially expressed in at least one of the atherosclerosis datasets taken in our 233 study (Table 1) (Table 2) . Both TLR2 and TLR4 256 have a common TG i.e. TNF in the COVID-19 network. Moreover, TNF is represented as a 257 common target of four DETFs -TLR2, TLR4, SPI1 and MYD88 (Table 2) . We have also 258 calculated the degree of the DETF's targets present in COVID-19 network using network 259 analyzer in Cytoscape 3.8.0. [38,39] to find out their impact in COVID-19. In this network, 260 TNF is found to hold the highest connectivity (v =109) indicating its strong influence in the 261 COVID-19 network. Being a pro-inflammatory cytokine, TNF has been shown to mediate 262 inflammatory response in atherosclerotic plaques [61] . Likewise, overexpression of cytokines 263 during SARS-CoV-2 infection is widely reported as severe COVID-19 patient hallmark i.e. The regulatory circuit in a biological system is tightly regulated and highly orchestrated. 290 Dysregulation in the higher order of a network might cause deregulation at the lower order. (Table 1 ) and all of these cytokines along with MYD88 are found to be significantly 306 overexpressed in comorbid dataset (Table 2) . Moreover, we have observed that IL1B, the 307 common target of three DETFs -IRF8, SPI1 and MYD88, is upregulated in this dataset. (Table 2) . Thus, 373 further experimental validation will help to confirm the role of TLR4 in eliciting 374 inflammatory response in these co-morbid patients. We found that EGFR encoding epidermal (Table 1) , but it is significantly 377 upregulated in SARS-CoV-2 infected cardiomyocytes (Table 2) . Interestingly, none of its 378 target genes are found to be differentially expressed in infected cardiomyocytes. Rather we 379 have noted a substantial number of targets of MYD88, SPI1 and IRF8 in COVID-19 network. 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