The host’s cellular receptors act as the recognition site for the viral spike (S) protein and work as the viral entry point into the host cell. In the case of SARS-COV 2, one of the major cellular receptors that facilitate viral inclusion is the Angiotensin-converting enzyme 2 (ACE 2) . The S protein of SARS-COV 2 has two subunits - S1 and S2. S1 binds to ACE 2, and S2 mediates the fusion of the virus with host cells . Recent publications have confirmed that overexpression of ACE 2 is associated with enhanced severity and enhanced susceptibility to the disease [73–75]. ACE2 converts Angiotensin-II (Ang II), a product of Ang-I conversion by ACE, into Ang-(1–7) in a normal human . In a COVID patient, internalization of the virus into the cells exfoliates the ACE2 and reduces its expression on cell membranes . This, in turn, increases the level of Ang-II and leads to the overproduction of cytokines like INF-\(\gamma ,\) IL-6, TNF-\(\beta\) etc. [78, 79] through JAK/STAT pathway and by inducing the Nuclear Factor kappa -B (NFκ-B), eventually causing Cytokine Storm in patients and deteriorate their condition . The accumulation of Ang-II can hyperactivate the Angiotensin-II type − 1 receptor (AT1R) and increase pulmonary capillary permeability, causing pulmonary oedema . Comorbidities can worsen the situation by increasing the Ang-II level further. For example, a COVID patient with type two diabetes has a higher blood IL-1\(\beta\) concentration, which increases the expression of ACE by elevating the expression of Hypoxia Inducing Factor-1\(\alpha\) (HIF-1\(\alpha\)) .
Several epigenetic conditions such as sex, food, smoking habit, and age have a role in controlling the expression of ACE-2 . Mostly male, aged, and smokers show hypomethylation in the ACE-2 gene and therefore, overexpression of ACE 2 makes them more vulnerable to COVID. On the other hand, Women, children and nonsmokers show hypermethylated ACE-2 gene; consequently, they are less susceptible to the disease . According to some studies, consuming polyunsaturated fatty acids increase the expression of ACE-2 and A Disintegrin and Metalloprotease 17 (ADAM 17) [85, 86]. Concurrent expression of both these genes reduces the expression of ACE 2 on the cell surface. Many epigenetic process processes, such as DNA methylation, telomere shortening, and especially DNA acetylation, are responsible for the expression and control of the ACE-2 gene .
ABO blood grouping antigen is also getting the spotlight as a parameter of COVID 19 severity. Several studies show evidence that ‘non-O’ individuals are at higher risk than individuals with the O blood group. However, the exact reason is still unknown [88, 89].
4.1 DNA Methylation:
Methylation of CpG island through DNA Methyl Transferases (DNMTs) silent the gene expression. Methylation at the promoter region prevents the binding of transcription factors and results in transcriptional inactivity. On the other hand, DNA demethylase removes the methyl groups and allows genes to express . Hypomethylation of two CpG regions (cg16734967 and cg23232263) of human lung tissues at the ACE 2 promoter region significantly differs in males and females, where females were found with more expressivity of the gene than males. Lysin demethylase KDM5B de- methylates H3K4me3 trimethylated Histone 3 residues which reduce the expression of mir-125a, followed by the upregulation of the ACE 2. Hypoxic condition is known to alter the functionality of several demethylases and therefore change the expression of the gene [91, 92]ACE 2 promoter methylation status in uterine corpus endometrial cancer and renal papillary cell carcinoma tissues are deficient, making them more susceptible to the SARS-COV 2. Similarly, Chronic Obstructive Pulmonary Disease (COPD) and smoking habits in the patient show CpG hypomethylation making the individual more prone to COVID .
DNA methylation status of other genes also has regulation over the COVID patient situations. For example, syncytin 1 and 2 are the two genes responsible for syncytium formation during placental development. SARS COV 2 also use the same genes to facilitate syncytium formation to enter the host cells and multiplicate. Generally, in other tissues than the placenta, these two genes are found to be hypermethylated. But in the case of viral infection, the genes become hypomethylated and facilitate the inclusion of the viral particles into the host cells [94, 95].
4.2 Histone acetylation and deacetylation:
Histone acetylation and deacetylation are the other significant modulators of epigenetic regulation of COVID severity. Adding acetyl group to the positively charged lysine residue neutralizes the overall positive charge of histone and allows the access of transcription factors to the genes . Histone acetylation and deacetylation work as the molecular switch to turn on and off the expression of genes and two types of enzymes which majorly play a role in this are Histone Acetyl Transferase (HAT) and Histone Deacetylase (HDAC) . Histone lysine acetylation activates the expression of ACE 2 receptors in humans. Hyper acetylation in histone 3 (H3AC) increases the H3K4 methylation . Several positively associated genes along with ACE 2 are also regulated by H3K27 acetylation. Studies have reported that HDAC can contribute to SARS-COV-2 pathogenicity in several ways – i) HDAC upregulates ACE2 expression and promotes viral entry to the cells . ii) HDAC activates pro-inflammatory responses against viral infections and may give rise to cytokine storms  iii) HDAC activity accumulates Acetyle Co-A, which elevates the cholesterol level . Increased cholesterol levels can promote viral entry to the cells. In stressed conditions, NAD-dependent HDAC Sirtuin-1(SIRT1) regulates the expression of ACE-2. Studies on SARS-COV 2 infected patients revealed that a higher transcription rate of ACE-2 can be stimulated by SIRT1. Even histone deacetylation may induce pulmonary fibroblasts formation in COVID − 19 survivors by altering the TGF-\(\beta\) signalling and ERK/PI3K pathway . HDAC7 plays a major role in TGF-\(\beta\) mediated fibroblast formation, which may cause mortality in COVID-19 patients. HDAC8 also induces fibroblast- myofibroblast differentiation in Idiopathic Pulmonary Fibrosis [103, 104]. According to studies, corticosteroids can downregulate the inflammatory gene expression by inhibiting HAT and recruitment of HDAC 2 . Unlike other HDAC, downregulation of inflammatory genes through HDAC 2 reduces the chances of the cytokine storm . HDAC 3 forms a multiprotein complex with a silencing mediator for retinoid and thyroid receptor (SMRT), nuclear receptor corepressor (NCOR) and suppresses the NF-K\(\beta\) activation by deacetylation of p65, which upregulates inflammatory genes such as IL-6, IL-1\(\beta\), TNF-\(\alpha\) etc. and can be a potential modulator of the cytokine storm . HDAC1 also is a regulator of NF-k\(\beta\) inactivity. Phosphorylation of HDAC3 by CK2 and HIPK2 can be a potential regulator of the cytokines storm. A high cholesterol diet (HCD) reduces the acetylation in the ACE 2 promoter region and increases the susceptibility of SARS- COV 2 infiltration inside cells . High-fat-fed mice treated with rhACE 2 shows a higher level of H3K9 acetylation . HDAC interventions are also found in viral trafficking via deacetylated microtubule and can be another aspect of COVID − 19 experiments.
4.3 Histone deacetylase inhibitors (HDACIs):
As histone deacetylation plays an important role in the expression of many genes responsible for the viral inclusions, several histone deacetylase inhibitors have been reported to downregulate ACE 2 expression, making it a potential modulator of COVID-19 and related cytokine storm. Saiz et al., in their in-vitro study, have shown that HDAC inhibitor Valproic acid (VPA) reduces ACE2 expression significantly  and Neuropilin-1 (NRP1) on the cell surface and the effect remains post-infection of SARS- COV-2 . Moreover, it reduces the inflammatory cytokine’s expression and production of infectious SARS-COV2 virus in a dose-dependent manner. In a clinical in-vitro experiment, using nine FDA-approved drugs to block the entry of constructed pseudotyped SARS-COV-2 virus. They found Romidepsin (drug ID: XJY-3), an HDAC inhibitor, significantly blocks the entrance of the SARS-COV-2 . The results suggest that HDAC inhibitors indirectly regulate viral inclusion in the host cells through SARS-COV-2 host protein-protein interaction, directly influencing the ACE 2 function. Invasion of SARS-COV-2 inside neuronal cells provokes neurological damage . In a cytokine storm, the blood-brain barrier gets destroyed in COVID-19 patients and may cause ischemic, hemorrhagic strokes . HDAC inhibitors show neuroprotective effects and downregulate the pro-inflammatory genes . Molecular docking of HDAC inhibitors against COVID-19 shows Romidepsin and its active form (RedFK) have great potential to bind to the binding site of viral protease CoVMpro and block its activity . It stops the virus from entering the host cells. Selective inhibition of HDAC6 reduces cytokine release by airway epithelial cells, monocytes and macrophages. HDAC inhibitors hinder the expression of INF-1 in both airway epithelial and immune cells, which helps counter the critical conditions of COVID-19 patients. Another experiment regarding the effect of HDAC inhibitors on suppressing ACE2, ABO blood antigen and TMPRSS2 expression have revealed that cells treated with Sodium Butyrate or Panobinostat suppress the expression of ABO and ACE 2 expression but not suppress TMPRSS2 . Therefore, HDAC inhibitors like panobinostat and sodium butyrate can be a potent therapeutic for COVID − 19. MirNet study has reported that HDAC inhibition can reduce the expression of ACE 2 followed by the reduction of SAR-COV-2 infectivity . Figure 2 describes epigenetic modulation of SARS-COV-2 and related cytokine storm (Fig. 2).
4.4 Telomere shortening:
Several studies of COVID- 19 cases have found that elderly individuals are at higher risk than young individuals. A shorter telomere length reduces the tissue regeneration, triggers the loss of specific homeostasis, normal functions of tissue and causes disease. Shorter telomeres are associated with increased disease severity and risk of developing severe COVID-19 pathology . Lymphopenia, a condition when the blood lymphocyte level goes down, is a hallmark of COVID − 19 prognostic and prediction. It is marked by low CD4/CD8 T-cells, which play a crucial role in viral infections . The reduction of T-cells causes more inflammation and results in the production of several cytokines. Immediate expansion and recovery of the T-cell pool, therefore one of the essential requirements for the recovery of COVID − 19. Lymphopoiesis is tightly associated with telomere length, and a shorter telomere length shows a slow proliferation rate of T- cells. Therefore, male or elderly individuals are at higher risk than females and young ones as they carry comparatively shorter telomere length. Apart from that, studies have reported that a short blood leukocyte telomere length can contribute to the development of lung fibrosis after SARS-COV-2 infections .