In a recent review published in the International Journal of Molecular Sciences, researchers examined the role of epigenetic modifications of the host cell gene expression in determining the pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). They explored using vitamin D as a therapeutic agent against coronavirus disease 2019 (COVID-19).
SARS-CoV-2 infections begin with the spike protein binding to the angiotensin-converting enzyme-2 (ACE-2) receptors on the host cell membrane, which activates downstream processes such as cleavage of the spike protein by serine proteases allowing the virus to release its genome into the host cell cytoplasm.
To evade the adaptive and innate responses launched by the host cell, many viruses have evolved mechanisms to reprogram the host cell. Epigenetic modifications such as deoxyribonucleic acid (DNA) methylation and histone modifications by the virus downregulate the expression of immune response-related genes while upregulating the host cell machinery needed for viral replications.
Besides osteogenesis, vitamin D also plays an important role in immune regulation. Lymphocytes and macrophages contain vitamin D-activating enzymes that maintain immune homeostasis. Vitamin D also activates beta-defensins and toll-like receptors during viral infections, which break down the viral membrane. Studies have shown that vitamin D downregulates the ACE-2 receptors. Vitamin D is epigenetically regulated via the vitamin D receptor (VDR).
COVID-19-related epigenetic modifications
The review discussed the current findings on the various epigenetic modifications that are thought to be involved in SARS-CoV-2 infections. DNA methylation is enabled by DNA methyltransferases and adds a methyl group to the fifth carbon of the cytosine nucleotide. Gene expression is silenced through hypermethylation and activated by hypomethylation. Studies have shown that ACE-2 gene expression is epigenetically modified, and age-related DNA methylation of the ACE-2 gene could increase the risk of COVID-19. Other studies provide evidence of hypermethylation of interferon genes and hypomethylation of pro-inflammatory and cytokine genes in patients with severe COVID-19.
Histone modifications result in the loosening or tightening of chromatin, aiding or hindering transcription, respectively. Studies showed that ACE-2-related genes were regulated by histone methylation and acetylation enzymes. Nicotinamide adenine dinucleotide-dependent histone deacetylase sirtuin 1 (SIRT1) enzyme, which modulates ACE-2 expression was found to be upregulated in severe COVID-19 cases. Increased intensive care unit (ICU) admittance has been associated with elevated histone H3 levels, and an increase in non-cleaved histone H3 is correlated to higher incidences of thromboembolic events.
Non-coding micro ribonucleic acids (miRNA) target the 3’ untranslated regions of messenger RNAs (mRNA), causing mRNAs to degrade. Viral miRNAs are known to target and degrade specific host mRNAs. Studies have identified differential expression of a large number of miRNAs in hospitalized and ICU-admitted COVID-19 patients. Furthermore, lower levels of specific miRNAs in hypertensive, obese, and diabetic patients were linked to increased susceptibility to SARS-CoV-2 infections.
Role of vitamin D in COVID-19
The active form of vitamin D, known as 1,25-dihydroxy vitamin D3, is synthesized by the enzyme 1α-hydroxylase enzyme (CYP27B1) expressed in the epithelia, which is the first line of defense against pathogens. Vitamin D deficiency has been linked to asthma and other chronic lung and obstructive pulmonary diseases. Supplementary vitamin D was seen to improve respiratory conditions in vitamin D deficient patients, and dietary vitamin D has been thought to control the genes that govern inflammation, immune responses, apoptosis, and cellular proliferation.
Heterodimers of VDR and retinoid X receptor (RXR) carry out epigenetic modifications by binding to the promoters of genes and recruiting transcription factors that activate or suppress genes. Vitamin D synthesis is also upregulated in antigen-presenting cells such as macrophages. Through antimicrobial peptide secretion and the activation of toll-like receptors, activated vitamin D also targets respiratory pathogens.
Studies investigating the association between SARS-CoV-2 infections and vitamin D deficiency found that over 75% of COVID-19 patients were deficient and a significant portion (85%) required ICU admission. A study across Europe found that countries with a high number of COVID-19-related deaths had prominent vitamin D deficiency.
Potential therapeutic avenues
While early research on COVID-19 therapies targeted the ACE-2 receptor and the SARS-CoV-2 spike protein, studies are now exploring chemicals that target the serine proteases. Camostat mesylate is a clinically approved serine protease inhibitor that was seen to repress the activity of transmembrane serine protease 2 (TMPRSS2).
Epigenetic enzymes are also a potential target for COVID-19 therapy. Current clinical trials are exploring the DNA methylation and transcription profiles of the immune cells of COVID-19 patients, and targeting the DNA methylation of ACE-2 and TMPRSS2 genes. Studies have also shown that resveratrol modulates SIRT1 activity.
To summarize, this comprehensive review reported the current findings on the roles of epigenetic modifications and vitamin D in the progression and treatment, respectively, of COVID-19. The authors also discussed potential therapeutic targets to limit COVID-19 severity.