South African Study Finds That COVID-19 Leads To Epigenetic Changes In Host Immune Genes Which Can Be Prevented Or Reversed By Vitamin D!
: Scientists from the College of Health Sciences, University of KwaZulu-Natal, Durban - South Africa have found that SARS-CoV-3 infections can lead to epigenetic changes in the human host immune response genes and that these epigenetic changes can be prevented or reversed by Vitamin D!
The ongoing COVID-19 pandemic has to date infected more than 636 million and killed more than 6.59 million people globally according to reported data. (In reality, the actual figures could be as high as 5 to 6-fold!)
Even with the emergence of a variety of new immune evasive Omicron variants and sub-lineages that health authorities around the world are claiming to be mild, COVID-19 remain a major threat worldwide especially with the elderly and comorbid individuals. Although vaccines are currently available, therapeutic drugs will help ease the viral outbreak and prevent serious health outcomes.
Epigenetic modifications regulate gene expression through changes in chromatin structure and have been linked to viral pathophysiology. Since epigenetic modifications contribute to the life cycle of the virus and host immune responses to infection, epigenetic drugs are promising treatment targets to ameliorate COVID-19.
The deficiency of the multifunctional secosteroid hormone vitamin D is a global health threat. Vitamin D and its receptor function to regulate genes involved in immunity, apoptosis, proliferation, differentiation, and inflammation.
Furthermore, accumulated research evidence also indicates the biological relations of vitamin D with reduced disease risk, while its receptor can be modulated by epigenetic mechanisms.
The immunomodulatory effects of vitamin D suggest a role for vitamin D as a COVID-19 therapeutic agent.
This COVID-19 Supplements
study highlights the epigenetic effects on COVID-19 and vitamin D while also proposing a role for vitamin D in COVID-19 infections.
The study findings were published in the peer reviewed Journal of Molecular Sciences.
This is the first study to examined in detail the role of epigenetic modifications of the host cell gene expression in determining the pathophysiology of the SARS-CoV-2 virus and also to explore using vitamin D as a therapeutic agent against the COVID-19 disease.
Typically, 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.
In order to evade the adaptive and innate responses launched by the host cell, many viruses have evolved mechanisms to reprogram the host cell.
It has been found that 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 ma
chinery needed for viral replications.
Unknown to many, besides osteogenesis, vitamin D also plays a critical role in immune regulation.
Most 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.
Past research has shown that vitamin D downregulates the ACE-2 receptors.
Vitamin D is epigenetically regulated via the vitamin D receptor (VDR).
Normally, 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.
Past research has also provided evidence of hypermethylation of interferon genes and hypomethylation of pro-inflammatory and cytokine genes in patients with severe COVID-19.
It should be noted that 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.
Interestingly, 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.
The 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.
Again, clinical studies have identified differential expression of a large number of miRNAs in hospitalized and ICU-admitted COVID-19 patients.
Also, lower levels of specific miRNAs in hypertensive, obese, and diabetic patients were linked to increased susceptibility to SARS-CoV-2 infections.
In the human host, 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.
To date, 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.
It is already known that 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.
Importantly, research 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 comprehensive study across Europe found that countries with a high number of COVID-19-related deaths had prominent vitamin D deficiency.
Although 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.
The epigenetic enzymes are also a potential target for COVID-19 therapy.
At present, there are ongoing clinical trials 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.
Interestingly, studies have also shown that resveratrol modulates SIRT1 activity.
The study review provides findings on the roles of epigenetic modifications and vitamin D in the progression and treatment, respectively, of COVID-19. The study team also discussed potential therapeutic targets to limit COVID-19 severity.
It should be noted that despite extensive studies that show the importance of Vitamin D in COVID-19 treatment protocols, there are still some researchers who probably under the payroll of certain pharma giants who keep on releasing manipulated studies or bias findings that claim that Vitamin D has no effect on COVID-19.
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