Scientists from China have recently deciphered the genetic network and biological mechanisms associated with coronavirus disease 2019 (COVID-19) myocarditis using bioinformatic methods. They have published their findings in the journal PLOS ONE.
A growing pool of evidence has highlighted the association between COVID-19 and myocarditis. The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of COVID-19, binds to the host receptor angiotensin-converting enzyme 2 (ACE2) to initiate viral entry. The organs with higher expression of ACE2, including lung, heart, and kidney, are, thus, particularly susceptible to SARS-CoV-2 infection.
According to the available literature, binding of SARS-CoV-2 spike protein to ACE2 results in downregulation of ACE2 expression, which in turn is responsible for tissue injury. For instance, a low level of ACE2 expression in the cardiac tissue is a known risk factor for heart diseases, including myocarditis.
In the current study, the scientists have conducted bioinformatics-based analysis to identify critical genes and biological pathways associated with COVID-19 myocarditis.
The scientists identified myocarditis-related genes by analyzing the datasets of SARS-CoV-2-infected cardiac stem cell and SARS-CoV-2-infected patients with myocarditis. They matched the identified genes with differentially expressed genes to identify the common genes.
To identify vital biological pathways related to COVID-19 myocarditis, they performed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) analysis for the common genes.
Differentially expressed genes in COVID-19 myocarditis
A total of 850 differentially expressed genes were identified. Of these genes, 449 were upregulated and 401 were downregulated.
A total of 10 co-expression modules, with each containing over 80 genes, were identified. Of these modules, one showed significant positive association with COVID-19 myocarditis. Based on the cut-off criteria set in the study, a total of 46 common genes with high connectivity in the module were identified.
Biological relevance of COVID-19 myocarditis-related genes
The GO analysis of genes revealed that the common genes are significantly related to the cell cycle/cell division pathways. Moreover, microtubule cytoskeleton and chromosome showed significant involvement in the common genes.
The KEGG analysis of genes revealed significant association of common genes with cell cycle, oocyte meiosis, progesterone-mediated oocyte maturation, ubiquitin-mediated proteolysis, and mismatch repair.
Protein-protein interaction network
A protein-protein interaction network between 46 common genes was prepared in the study. A bioinformatics-based analysis of the network identified six critical genes related to COVID-19 myocarditis.
Considering these critical genes, transcription factor-gene and transcription factor-miRNA networks were identified. A total of 25 miRNAs and 64 transcription factor genes were identified that co-regulated the critical genes.
Target drugs for COVID-19 myocarditis
As mentioned by the scientists, identified critical genes could act as potential biomarkers for the diagnosis and treatment of COVID-19 myocarditis.
Considering the critical genes, COVID-19 myocarditis-related drugs were identified from the Drug Signatures Database, which is a gene-set resource that relates drugs to their target genes. Based on the statistical significance, ten COVID-19 myocarditis gene-targeted drugs were selected, including Etoposide, Methotrexate, Lucanthone, Troglitazone, Ciclopirox, STL264925, Thalidomide, Genistein, Dmnq, and Testosterone.
Among these drugs, Etoposide, Methotrexate, and Troglitazone have been found to have anti-SARS-CoV-2 effects, including inhibition of viral replication and suppression of infection-related hyperinflammation (cytokine storm).
The study identifies six critical genes related to COVID-19 myocarditis, including cyclin-dependent kinase 1 (CDK1), kinesin family member 20A (KIF20A), PDZ binding kinase (PBK), kinesin family member 2C (KIF2C), cell division cycle 20 (CDC20), and ubiquitin conjugating enzyme E2 C (UBE2C). These genes might serve as potential biomarkers for the diagnosis of COVID-19 related myocarditis.
Moreover, the study reveals that SARS-CoV-2 increases the risk of myocarditis by modulating a number of biological processes including cell cycle and ubiquitin-mediated protein hydrolysis.
Importantly, the study identifies top ten drug compounds that may have potential therapeutic impact on COVID-19 related myocarditis.