Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of the current pandemic, coronavirus disease 2019 (COVID-19) (17). This pathogen is enabled by the angiotensin-converting enzyme 2 (ACE2) (18). Mechanistically, SARS-CoV-2 penetrates and enters the host cell by binding to the ACE2 receptor as the primary target. This is facilitated by proteolytic priming by the cellular transmembrane serine protease 2 (TMPRSS2) (19). In the proposed model of respiratory failure, SARS-CoV-2 downregulates ACE2 through the SARS-CoV spike (SARS-S) protein, explaining the renin-angiotensin-aldosterone systems (RAAS) dysregulation and cardiotoxicity in severe COVID-19 infection (20). Suppression of ACE2 also induces tumour necrosis factor alpha (TNF-α) converting enzyme (TACE) that antagonises ACE2 shedding of the SARS-S (19). Modulation of TACE activity by SARS-S protein was found to depend on the cytoplasmic domain of ACE2 as ACE2 mutants devoid of the carboxyl-terminal region could not induce ACE2 shedding or TNF-α production (21). Moreover, deletion of the cytoplasmic tail of ACE2 or knock-down of TACE expression significantly attenuates viral infection (21). It has been shown that Ang II induces ACE2 shedding by promoting TACE activity as a positive feedback mechanism, suggesting that SARS-CoV mediated ACE2 down-regulation will promote Ang II accumulation and HIF-1α activation, which positively activates disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) activity, thus perpetuating membrane shedding of ACE2, RAAS overactivation, and inflammation (22–26). This mechanism, however, is not universal to all coronaviruses because the spike protein of HNL63-CoV (NL63-S), a coronavirus that also utilizes ACE2 and is known to cause common influenza, did not produce similar cellular responses (21).

DNMT1, DNMT3A, DNMT3B, and DNMT3L are family of DNMTs that write or deposit methylation on DNA leading to hypermethylation, read by MBDs to mainly suppress gene transcription ( Figure 1 ) (4, 154). DNMT1 binds to and methylates hemi-methylated CpG sites to ensure stable maintenance of DNA methylation (4). DNMT 3A and 3B are de novo methyltransferases that mainly lead to transcriptional repression through the establishment of non-CpG methylation, an emerging epigenetic mark that defines brain tissue-specific patterns of gene transcription (155–159). DNMT3L is catalytically inactive and serves as a cofactor for DNMT 3A and 3B (160, 161).

Although DNA methylation patterns are erased and deposited through successive normal developmental stages and cell differentiation, they also occur in the form of epigenetic memory in stem cells, and in communicable and non-communicable diseases, reviewed in (162). Most importantly, various epigenetic phenomena triggered in response to raging viral replication are usually hijacked by the same targeted virus to alter the protective immunoregulatory mechanisms for survival and propagation, reviewed in (163). For instance, during infection with hepatitis B virus (HBV), DNMTs are upregulated in response to productive viral replication mediated by the host-viral interaction as part of host immune defence mechanisms, also reviewed in (164). In the long run, the same DNA methylation machineries may start hypermethylating CpG island promoters that overlap with host-viral integration sites leading to alteration in the transcription of genes, including immunoregulators and tumour suppressors that are critical to carcinogenesis (164). COVID-19 related airborne respiratory infections such as the Middle East respiratory syndrome-CoV (MERS-CoV) and avian influenza (H5N1) have also been shown to exploit DNA methylators and histone modifiers to suppress immunoregulators such as type 1 IFN-γ-responsive genes. These genes include class II, major histocompatibility complex, transactivator (CTIIA), antigen peptide transporter 2 (TAP2), and protein disulfide-isomerase A3 (PDIA3) (165). Abnormal regulation of these genes impedes the host immune system to fight infections effectively (166). This suggests that various epigenetic reprogramming phenomena may also occur during COVID-19 infection (167).

Mice transfected with hACE2 and subsequently infected with SARS-CoV-2 have been used to gain insights into epigenetic changes that drive cardiac injury in COVID-19 patients (153, 168). Li and colleagues identified 172 differentially methylated CpG sites in the hearts of SARS-CoV-2-infected mice compared with controls (153). Two genes, paternally expressed gene 10 (Peg10) and endothelin-converting enzyme 1 (ECE1), show high levels of differential methylation in SARS-CoV-2 mice bearing hACE2 compared with controls. For the Peg10 gene, a hypomethylation pattern consistent with higher expression of the Peg10 gene in hearts was seen. The loss of function of the Peg10 gene is known to result in early embryonic death (169). Peg10 gene also regulates cellular proliferation and viral replication through binding to the viral transcription regulators (170). SARS-CoV-2 infection was associated with increased methylation of the ECE1 gene, the product that regulates proteolysis of endothelin precursors to form biologically active peptides (171). Loss of function of the ECE1 gene is associated with cardiac defects, generalized oedema, and autonomic dysfunction (172). In another study, blood samples from acute SARS-CoV-2 infection versus healthy controls blood samples exhibited 28% of hypermethylated regions (173). Hypermethylated regions comprised of more than 5 consecutive differentially methylated CpG sites. It is not surprising that studies with SARS-CoV-1 and MERS also detected differentially methylated CpG sites, and found to be located in the promoter regions encoding genes involved in interferon and antigen presenting cells stimulation (174). This supported a recent study that identified >40 CpG sites encoding genes serving similar purposes, suggesting the role of DNA methylation influencing COVID-19 progression and target for epigenetic therapy (175).

Activation of the immunoregulatory cytoplasmic transcription factor aryl hydrocarbon receptor (AHR) may also result in hypermethylation that contributes to COVID-19 pathogenesis. The AHR has been identified as a host factor for Zika and Dengue viruses, and its inhibition was associated with significantly reduced viral replication and amelioration in the disease pathology (176–178).

It has been shown that the AHR becomes activated upon SARS-CoV-2 infection (178), and that it impacts SARS-CoV2 antiviral immunity and pathogenesis, promoting a pro-inflammatory response and participating in the severity of COVID-19 (178). Furthermore, it has been postulated that AHR activation may be the culprit behind the COVID-19-mediated cytokine storm (145, 178, 179). RNA-Seq analysis of CoV-infected cells unveils an upregulation of the AHR and its target genes, including AHRR and CYP1A1 (177). Kynurenic acid, a product of normal metabolism of L-tryptophan, and a potent endogenous AHR ligand, has also been shown to be elevated in response to COVID-19 (139, 180). This correlated with cytokine storm, age and low levels of T-cell responses, especially in males as compared to female patients, hinting for a sex-specific link to immune response and COVID-19 clinical outcome (139). Curiously, activation of the AHR has been associated with hypermethylation in acute lymphoblastic leukaemia (ALL) in vitro. When demethylated by methylation inhibitor zebularine, AHR-related methylation inhibition restored normal cells phenotype and prevented tumorigenesis (181). In another study, AHR activation resulted in epigenetic alteration of Foxp3 and IL-17 expression and consequently attenuated colitis (182). Recently, Jiadi et al. (183), have shown that macaques infected with SARS-CoV-2 modulation of the AHR upregulates the expression of ACE2 by binding to its promoter regions, and this is accompanied by aggressive disease. Consequently, if the AHR becomes hypermethylated, as shown in other pathologies, the level of ACE2 may also be silenced through the same methylation. This may disrupt the inhibitory mechanisms regulated by ACE inhibitors or other RAAS blockers leading to the aggressiveness of underlying cardiovascular diseases (e.g., hypertension) that have been reported in severe/critical cases of COVID-19 infection.

Interestingly, the AHR also regulates the expression of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), that may also be epigenetically regulated (184, 185). Castro de Moura et al., revealed a strong correlation between COVID-19 clinical severity and DNA methylation of 44 CpG sites with >50% of these located in 20 promoters of annotated coding genes including Absent in Melanoma 2 (AIM2) and major histocompatibility class 1C (HLAC) (175). AIM2, similarly to the NLRP3, is part of the inflammasome complex (186). The inflammasome is involved in caspase-1 cleavage, trigger of gasdermin D-mediated pyroptotic cell death and release of pro-inflammatory cytokines IL-1β and IL-18 in response to pathogens’ insult, reviewed in (187, 188). Altered levels of IL-1β and IL-18 cytokines were observed in COVID-19, as it does in several male infertility-related disorders such as varicocele (49, 111, 189), suggesting that NLRP3 may also be activated upon COVID-19 infection. This notion is supported by the study of Su et al. (190), that demonstrated that upregulation of calcium-sensing receptor (CaSR) activates the NLRP3 pathway in testicular macrophages and impairs testosterone synthesis in a uropathogenic Escherichia Coli (UPEC) rat orchitis model.

Chronic infections such as HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) have been demonstrated to infect sperm cells and trigger oxidative stress. Subsequently, this activates histone modifications leading to long-term effects on male fertility parameters such as sperm integrity, count, motility, and morphology. During normal differentiation, sperm cells’ genome undergoes successive rounds of epigenetics marks to ensure proper spermatogenesis and spermiogenesis (191). More than 85% of human mature sperm cells’ DNA is bound to protamines. Protamines are sperm-specific basic nuclear proteins that take over the histones’ position and function to package the sperm DNA for compaction necessary for sperm motility (192). In the late stages of spermatogenesis, sperm cells’ genome becomes dramatically reorganised and globally hyperacetylated to remove and replace histones with protamines. This phenomenon essentially erases the epigenetic modifiers laid out through histone modifications. It preserves the paternal genome by protecting it from extracellular stressors and harmful effects of the oocyte during fertilisation (192). An altered protamine ratio or histone content or distribution in sperm is a sign of aberrant chromatin packaging, associated with increased susceptibility to DNA damage or abnormal epigenetic marking that may lead to male infertility. Ma et al. (108), have detected SARS-CoV-2 in the testis’ biopsies of COVID-19 patients. Immunohistochemistry analysis revealed a significant increase in spermatogenic epithelial shedding in the deceased patients with critical cases of COVID-19, which was accompanied by thinning of seminiferous tubules (193). Inflammation of the epididymis and/or testicle was associated with old age (>80yrs) and severe or critical cases of COVID-19 (P = .037) (107). More than 20% of recovered patients who previously had children through natural birth exhibited autoimmune orchitis. This was indicated by observed oligospermia, leukocytospermia, elevated sperm phagocytic CD3+/CD68+ immune responses in testes/epididymis and apoptotic cells relative to age-matched control males (193). In some cases, tocilizumab was administered in response to a progressive worsening of oxygenation, and blood biochemistry tests revealed an elevation of lactate dehydrogenase to 1213 U/l, D-dimer to 1150 ng/ml, and CRP to 23.80 mg/dl. Impaired spermatogenesis and increased apoptotic cells may be attributable to COVID-19-induced histone modifications associated with elevated CRP and fever that perturbed the optimum testicular temperature (2 – 4 ⁰C below the average body temperature) (194). Moreover, extensive germ cell destruction, as demonstrated by the TUNEL assay, may have also been a contributing factor.

TETs are regarded as erasers of DNA methylation, reviewed in (195). They actively or passively demethylate DNA methylation by removing the 5-methylcytosine mark. TETs oxidise 5-methylcytosine to generate 5-hydroxymethylcytosine (5-hmc), 5-formylcytosine (5-fc), and 5-carboxycytosine (196–198). 5-hmc is a stable epigenetic mark that is highly abundant in the brain, liver, and stem cells, and it is crucial for neurogenesis and hepatocellular carcinoma (HCC) (199, 200). TETs are prominent regulators of immune cells. For example, Tet-2 mediates T-cell differentiation and synergises with Tet-3 to modulate the expression of Foxp3, a transcription factor responsible for T-cells development (201). Tet-deficient mice CD4-T cells exhibited impaired Th1/2/17 differentiation and cytokine production in lymphocytic choriomeningitis virus infection, supporting a critical role of Tet-2 in infections (202). In other studies, loss of Tet2/3 resulted in an antigen-driven expansion of various immune cells and rapidly developed aggressive disease phenotype (203, 204). Moreover, combined deletion of Tet2/3 in mice exhibited impaired Treg cell differentiation. This was accompanied by DNA hypermethylation of various Treg-specific demethylated regions (TSDRs) within the Foxp3 locus that resulted in aberrant Foxp3 expression (205, 206). TNFs and ILs, important cytokine storm elevated markers observed in severe or critical cases of COVID-19, are known to induce DNA demethylation via TETs (207–210). IL-1β and TNF-α modulate the global hydroxymethylation by activating TETs and iso-citrate dehydrogenases in the genomic DNA and specific locus in matrix metalloproteinase (MMP) promoter region in human OA chondrocytes (211).

In severe COVID-19 pneumonia cases, abnormal upregulation of T-cell proliferation, activation, and cytotoxicity was noted at the late phase of infection, suggesting an underlying perturbation resulting in the loss of an inhibitory role Tregs (212). Mohebbi et al. (210), have shown that CD4+ FoxP3+ CD25+ T cells expression level is significantly suppressed in hospitalised COVID-19 patients and led to an elevated level of IL-6. Given this evidence, it is intriguing to suggest this aberrant hyperactivation of cytotoxic cells in COVID-19 may be attributable to Tet-2/3-mediated epigenetic regulation of Tregs. Cell division occurring as a result of antigen and cytokine stimulation in response to COVID-19 infection may be the underlying mechanism for this epigenetic reprogramming. This may result in aberrant gene transcription, fatal inflammatory response, disease aggressiveness, and multi-organ disease phenotypes observed in severe and critical cases of COVID-19.

Abnormal production of the IFN and IFN-γ correlate with slowly resolved COVID-19, and enhanced viral replication was also observed, as previously reported in other studies (213–215). This may also correlate with genetic variation of heat shock protein 70 (HSP70) or A1L (HSPA1L), which has been demonstrated to result in significantly higher plasma concentrations of TNF-α and IL-6 and poor clinical outcomes after severe tissue injury from pathogens (216). Elevated levels of TNF-α and IL-6 are associated with severe cases of COVID-19 and systemic inflammation, as well as HSPA1L gene upregulation via hypomethylation of its promoter regions in response to increased SARS-CoV-2 viral replication (217). HSPA1L hypomethylation is catalysed by the dramatically reduced DNA methyltransferases (DNMT 1 - 3), possibly via TETs and postulated to enable viral cell entry and protein synthesis (217, 218).

Histone lysine acetylation is catalysed by conserved histone acetyltransferases (HATs) and plays a crucial role in viral infections (219, 220). It facilitates the transfer of an acetyl functional group from acetyl coenzyme A to the ε-amino group of the lysine residue at one end of the histone molecule on the chromatin. HATs alter the charge of various lysine residues within either H3 (histone acetylation at lysine 9, 14, 18, and 23, denoted as H3K9/14/18/23ac) or H4 (H4K5/8/12/16ac), reviewed in (221–223). A positive charge from lysine becomes neutralised by a negative charge from a transferred molecule, reducing the binding affinity between histones and DNA. This alters the chromatin architecture by opening the chromatin and making it accessible to the transcription factors for active gene expression (221–223). MYST writes histone acetylation, adenoviral E1A-associated protein of 300 kDa/CREB-binding protein (p300/CBP) and general control non-derepressible 5 (GCN5)-related N-acetyltransferases (GNATs) and read by bromodomains (BRD) and extra-terminal (BET) family of proteins (221, 222).

Histone H3 and H4 form a significant component of the host immune defence mechanism against pathogen insults and other hostile environments. In vitro studies with retroviral infected mouse embryonic fibroblasts have shown that histones are loaded rapidly on unintegrated retroviral DNA soon after infection (219, 220). Unintegrated retroviral DNA is typically weakly expressed, but in response to interaction with loaded histones, their expression may become dramatically increased by chromatin modifiers and promote persistent infection (219, 220). Several studies have shown that histones can be released into blood circulation during an infection as damage-associated molecular patterns (DAMPs) from apoptotic and damaged cells, eliciting an inflammatory stimulus (224–226). DAMPS interact with TLRs, and trigger TLR/myeloid differentiation factor 88 (MyD88)/NLRP3 pathways leading to activation of macrophages (227). This, in turn, can cause an accumulation of neutrophil infiltration and subsequent production of neutrophil extracellular traps (NETs) and reactive oxygen species (ROS) (227). Activation of TLR/MyD88/NLRP3 pathways has been upregulated in obese patients that are at high risk of severe COVID-19 infection (228). This suggests that activating these pathways by the DAMPs and histones loaded on viral proteins may be the mechanism underlying an excessive tissue inflammation and injury that correlates with multiple organ failure and increased mortality in COVID-19 infection.

Histones can also bind to complement component 5a (C5a) and CRP, which are proteins expressed by the liver in response to systemic inflammation (229–231). CRP is a regulatory factor for angiogenesis and thrombosis associated with cardiovascular disease (CVD), which is a risk factor for COVID-19 severe cases (232). An elevated level of C5a and CRP in COVID-19 infection is an indication of excessive inflammatory response in endothelial cells and tissue damage that correlates with aggravated disease or poor prognosis. Neutrophils play an important role in the early or later stages of severe cases of influenza A virus (IAV), and COVID-19 infection cases, where circulating cell-free histones are enriched and highly pro-inflammatory (233). Hsieh et al. (233) have shown that binding of histones H4 to CRP in neutrophils models infected with IAV blocks the H4-mediated neutrophil activation and potentiates neutrophil inflammatory response during infection (233). This data suggests that H4 may be part of the host protective mechanism during excessive pro-inflammatory response. However, in response to interaction with circulating virus through molecules such as C5a and CRP, this mechanism may be hijacked by the virus for its replication advantage leading to tissue damage and fatal sequelae observed in COVID-19.

A case study of four unrelated young men who were critically ill with COVID-19 infection, and subjected to mechanical ventilation in the ICU, revealed nonsense and missense X-chromosomal TLR7 variants using whole-exome sequencing (213). This TLR7 variant mutation resulted in a unique loss of function from aberrant alteration of TLR7 mRNA expression and its downstream target genes. Interferons regulatory factor 7 (IRF7), interferon beta 1 (IFNB1), and interferon stimulated gene 15 (ISG15) are examples of genes associated with this TLR7 variant mutation. IRF7 becomes acetylated by HATs p300/CBP-associated factor (PCAF) and GCN5, and this usually impairs its binding activities leading to reduced IRF7 activity. PCAF acetylase complex and GCN5 are required for viral integration, and they have also been shown to be activated in influenza A virus to negatively regulates the viral polymerase activity (234, 235). PCAF is also known as lysine acetyltransferase 2B (KAT2B), a master regulator of TGF-β signalling pathway that triggers CVD development when altered. The SARS-CoV-2 virus induces an aberrant and excessive TGF-β-mediated chronic immune reaction creating a switching from IgM to IgA1 and IgA2 immunoglobulins (38, 236). This, in turn, causes an increased pro-inflammatory response and severe disease activity that correlates with prolonged ICU COVID-19 cases and fatalities (38, 236). It is important to investigate the possible roles of PCAF and GCN5 activities in regulating TGF-β and TLR7 signalling pathways in severe COVID-19 for novel treatments to ameliorate the severity and prevent COVID-19 fatalities.

Unlike histone acetylation, histone methylation does not modify any histone protein charge but deposits one or a set of methyl groups from S-adenosyl methionine (SAM) on the side chains of either H3 or H4 lysines or arginine (237). Histone methylation is catalysed by histone methyltransferases (HMTs) with various methylation sites (238). One of these HMTs is SET1B with H3K4me3 occupancy on open chromatin, and this recruits transcription factors for epigenetic transcriptional activation (239). This epigenetic tag has been shown to induce hypoxia, one of the emerging key drivers of COVID-19 pathogenesis and related fatalities. COVID-19 related-hypoxia manifests insufficient levels of oxygen supply in various tissues. SET1B activation is oxygen-dependent and facilitates hypoxia responses via site-specific histone methylation (240). In response to hypoxia, SET1B is recruited to the hypoxia-inducible transcription factor (HIF) promoter via HIF1α and facilitates the expression of genes involved in angiogenesis (240), one of the clinical features of COVID-19 severity. HIF-related genes will be described further in a later section of histone demethylation.

Histone acetylation and methylation are erased by HATs and lysine demethylases (KDMs)/lysine-specific demethylases (LSDs), respectively. The former result in a more condensed, closed, and transcriptionally silenced chromatin structure that is not accessible to transcription machineries (6–10). The latter blocks the recruitment or occupancy of transcriptional factors on the chromatin sites (9). The process is called histone lysine deacetylation or demethylation, and it associates with the repression of gene transcription. HDACs are grouped into four classes, including class I (HDACs 1 - 3 & 8), class II (HDACs 4 -7, 9 & 10), class III (Sirtuin 1 - 7) class IV (HDAC 11), reviewed in (241, 242). KDMs/LSDs include KDMs/LSDs 1 – 6 with several families that act on different substrates for various cellular processes.

Histone repression marks are common phenotypical features in viral infections and other diseases, such as cancer (243). Virus-induced cancers from HBV, HPV, and EBV hijack histone acetylation marks for viral survival and propagation, and various HDACs inhibitors have been shown to circumvent these effects and alleviate the disease (244–247). Sirtuin 1 (SIRT1) is a key epigenetic regulator of CVD, metabolic and age-related disease through interaction with nuclear transcription factor-κB (NF-κB), a master regulator of inflammation activated by a signal transducer and activation of transcription 3 (STAT3) (248, 249). STAT3 becomes hyperactivated and impairs immune defence machineries that promote exacerbated inflammation and lymphocytopenia, leading to lung fibrosis and thrombosis, as demonstrated in severe COVID-19 cases (249). SIRT1 was also shown to interact with and modulate p53 activities to regulate viral replication in MERS-CoV and SARS-CoV infections (250, 251). Takahashi et al. (252), have recently shown that panobinostat, an inhibitor that counteracts HDACs effects, silenced the transcription of ACE2 receptor and ABO gene (gene encoding three blood group alleles) in cultured epithelial cell lines. This suggested a potential preventative drug against COVID-19 infection (252, 253). ACE2 is the primary host receptor for viral entry, whereas the ABO blood group system has been suspected to increase susceptibility for severe COVID-19 cases (252, 253). Related to this, Zhao et al. (254), have shown that blood group A individuals may be susceptible to COVID-19 infection, owing to the enrichment of group A antigen in respiratory cells (254).

Upregulation of HDACs by hypoxia was shown to be activated in response to a silence in hypoxia-responsive tumour suppressor genes (255, 256). These genes include HIF-1α and vascular endothelial growth factor (VEGF), and their epigenetic-mediated alteration correlates with a dramatic increase of intussusceptive angiogenic features (255). A similar clinical phenotype was observed in the lungs of deceased COVID-19 patients, exhibiting distinctive pulmonary vascular pathophysiologic features in a background of perivascular inflammation and injury, as relative to those of influenza (257). VEGF is a prominent mediator of angiogenesis and is usually involved in wound healing (257). VEGF exerts its activities through VEGFR 1–3, which are targeted and negatively regulated by epigenetics alterations (258). VEGFR3 receptor has two ligands, VEGF-C and VEGF-D, which stimulate angiogenesis. Interestingly, serum levels of VEGF-D were found to be significantly elevated in ICU COVID-19 patients as compared to non-ICU patients, a novel biomarker to trace the progression of disease (258). Current research shows that VEGF and its associated receptors undergo histone deacetylation, suggesting them as potential epigenotherapy targets. It has previously been shown that histone deacetylase 4 (HDAC4) remodels neuronal morphology by altering the transcription signature of VEGF-D (259). Activation of HDAC2 suppresses inflammatory cytokines (e.g., IL-17, Figure 4 ) in pulmonary disease, and this with the disease onset and sometimes with prognosis (260–262). On another note, Ahmad et al. demonstrated that endothelial TLR/MyD88 signalling is regulated by histone deacetylase 6 (HDAC6), contributing to alveolar remodelling architecture and pulmonary inflammation (263). Upregulation of TLR/MyD88 signalling pathway in association with elevated TNF-α and IL-6 was reported in overweight and obese individuals as compared to lean individuals (263). In referral to this observation, Cuevas and co-authors have recently published a brief communication postulating and probing for a research study that upregulation of TLR/MyD88 signalling pathway may contribute to excessive and fatal pro-inflammatory cytokine storm especially in SARS-CoV-2 vulnerable obesity individuals (228). MyD88 was shown to establish and promote CD4 T-cells responses to control viral spread to the central nervous system (CNS) in coronavirus-induced encephalomyelitis (228). Any abnormal regulation of MyD88 signalling already existing in obese individuals and other co-morbidities may impact COVID-19 disease progression leading to more fatalities (228).

The widespread methylation of genes in SARS-CoV-2 infection is associated with the downregulation of genes involved in the regulation of the tricarboxylic acid (TCA) and mitochondrion electron transport chain (153). SARS-CoV-2-induced epigenetic alterations interfere with metabolic processes that are core to generating energy for the myocardium (153). The perturbed metabolic processes restrict the energy required for uncontrolled systemic inflammatory response leading to myocardial injury. Transcriptome analysis studies conducted from patients with hypertension and DM associated with severe COVID-19 cases revealed that ACE2 expression was potentially regulated synergistically by various histone marks such as histone acetyltransferase 1 (HAT1), HDAC2, and lysine demethylase 5B (KDM5B) (264). KDM5B is a histone H3K4me2/3 demethylase that is associated with therapeutic resistance in cancer (264). Hinohara et al. (264), demonstrated that inhibition of KDM5B increases sensitivity to endocrine therapy by modulating oestrogen receptor, suggesting the therapeutic potential of this epigenetic demethylating mark. Concerning viral infections, KDM5B was shown to suppress stimulator of interferon genes (STING), a cytosolic DNA sensor that activates downstream transcription factors signal transducer and activator of transcription 6 (STAT6), and interferon regulatory factor (IRF3) through TANK-binding kinase 1 (TBK1) (265). This, in turn, protects the host cells by eliciting an antiviral response and innate immune defence against intracellular pathogens and cancer (265). SARS-CoV proteins were shown to interact with STING and activate the STING-TRAF3-TBK1 complex leading to abnormal alteration and inhibition of type 1 IFN activities that may be associated with severe disease (266). 3C-like (3CL), the main protease and regulator of viral replication for SARS-CoV-2, was shown to inhibit the activation of immune defence machinery by perturbing both RIG-I-like receptors (RLR) and cGAMP binds to stimulator of interferon genes (C-GAS-STING) pathways in human lung cells, suggesting a mechanism that will enable the virus to replicate more efficiently during infection (267). Upregulation of STING and aberrant activities usually correlate with cytokine storm in older people and those who suffer from metabolic disorders (268–271). This may explain the increased COVID-19 severe cases in patients who are older, diabetic, and hypertensive.