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2021.06.02.31
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REVISION/REVIEW

Major epigenetic factors associated with the novel coronavirus disease-2019 (COVID-19) severity
Ahmed A Mhawesh1, Daniah Muneam Hamid2, Abdolmajid Ghasemian3
Available from: http://dx.doi.org/10.21931/RB/2021.06.02.31

ABSTRACT

The worldwide spread and high rate of viral transmission and related morbidity and mortality of Coronavirus disease-19 (COVID-19) is a crisis. Some epigenetic determinants predispose individuals to severe infection. Patients with prior chronic medical illnesses (hypertension, diabetes, lupus, and chronic obstructive lung disease) are highly susceptible to the infection. The aging and diabetes pandemic possibly exacerbate the COVID-19 or SARS-CoV-2 pandemic by enhancing COVID-19 associated comorbidities. COVID-19 utilizes several proteins for tackling the host immune response associated with enhancing comorbidities. The angiotensin-converting enzyme (ACE) is a significant receptor for SARS-CoV-2, which significantly expresses higher among individuals with comorbidities and under stress conditions. Patients with systemic lupus erythematosus are also prone to be susceptible to the disease. Viral infections cause a defect in the DNA methylation in lupus, causing further ACE2 hypomethylation and overexpression, leading to viral binding and cytokine storm and tissue damage during COVID-19 infection. The microRNAs (miRNAs) epigenetics regulations also play a critical role in the suppression of immune responses.
Meanwhile, viral proteins interplays with the host cell are conferred primarily through TGF-β and HIF-1 signaling, endocytosis, autophagy, and Toll-like receptor signaling RIG-I signaling, Il-17 signaling, and fatty acid oxidation/degradation. Furthermore, the COVID19 patient's metabolic states determine the infection severity. Noticeably, ten human metabolic proteins, including SGTA, SPECC1, FGL2, PHB, STAT3, BCL2L1, CAV1, JUN, PPP1CA, and XPO1, interact with the SARSE-CoV-2. Interactions between SARSCoV's spike protein-containing lipid-rich membrane compartments and epigenetic modulations are considered targets to inhibit the viral infection. Therefore, it seems that epigenetics plays a substantial role in the COVID-19 severity. Future in-depth studies will be promising. Vaccine design, particularly regarding ACE viral receptor monoclonal antibodies, is a proposal alongside adhering to personal hygiene.
Keywords: Coronavirus disease-19, epigenetics, severe respiratory disease
 

INTRODUCTION

For fighting against every infection, a triangle including genetics, environment, and lifestyle is the primary determinant of triumph. The recent emergence and spread of novel Coronavirus disease known as COVID-19 or Severe Acute Respiratory Syndrome Coronavirus-2 (SARSE CoV-2, also coronavirus) in Wuhan in central China, has recently caused a pandemic scale of pneumonia in humans leading to concurrently and continuing high transmission, morbidity and mortality rat 1 Coronavirus subfamily is single-stranded positive-sense (+ssRNA) virus. The pandemic spread of novel coronavirus disease-19 (CoVID-19) in 2019-2020 originated from Wuhan, China, continues to affect human health and many life aspects and activities. The severity of infection increases with advancing age. Data suggests that very complex host-virus interplays occur during the SARS-CoV-2 infections (table1 and Figure 1).
Although the pathogenicity of SARSE-CoV-2 has not been entirely understood, extensive lung damage, enhanced infiltration of monocytes, macrophages, and neutrophils within the respiratory system and the blood storm of proinflammatory cytokines and chemokines are associated with the severity of infection 2, 3. Another mechanism of viral evasion includes delayed IFN type I transduction which stimulates the monocytes and macrophages and delays T-cells activation. Both the SARSE-CoV and SARSE-CoV-2 viruses bind to the angiotensin-converting enzyme receptor (ACE) via their spike protein receptor-binding domains which share 72% amino acid similarity 4, 5. Strikingly, the SARSE-CoV-2 domain has an incredibly higher receptor affinity. Higher expression of ACE among patients with comorbidities supposedly predisposes them to severe infection.
Moreover, it was stated that viral binding to the ACE downregulates its expression and leads to lower level biosynthesis of end-product vasodilator heptapeptide angiotensin 1-7. This, in turn, causes lung injury due to increased pulmonary vascular permeability. Another receptor for Coronaviruses includes a zinc peptidase known as aminopeptidase N (APN), which shares homology and membrane topological similarities with the ACE 4, 6, 7.


Table 1. Major Coronavirus non-structural proteins (nsps) and their pathogenicity capabilities
 
   
Those epigenetic factors mainly facilitating the viral attachment to host cells seem to enhance the death rate. These primarily include methylation or expression of angiotensin-converting enzyme 2 (ACE2), microRNAs regulation, metabolic conditions, individual behavior (such as smoking), and some environmental conditions (temperature and humidity) 37-39.
 


Figure 1. Genome and non-structural proteins of Severe Acute Respiratory Syndrome Coronavirus-2.

The genomic material released by its virus is mRNA, so it is prepared to stay translated into protein. In its genome range, its virus is complemented by using respecting 14 open reading frames (ORF), each of which encodes a variety concerning proteins, each structural yet non-structural, so move a function into its uplift so nicely as much virulence power. In its transformation section, the gene segments so encode non-structural polyproteins use this method to advance ORF1a yet ORF1b under production twins full-size overlapping polyproteins, pp1a and pp1ab utilizing contributing a ribosomal body shifting match 40 . The polyproteins are supplemented by using protease enzymes, specifically papain-like proteases (PLpro), yet a serine kind Mpro (chymotrypsin-like protease (3CLpro)) protease as are encoded of nsp3 then nsp 5. Subsequently, burst occurs into pp1a yet pp1ab into non-structural proteins (nsps) 1–11 and 1–16. The nsps shed a vital role in deep approaches of viruses yet host cells, as shown in Table 1. 2
 
Angiotensin-converting enzyme as the CoVID-19 receptor
Several body compartments, such as respiratory and gastrointestinal systems, have cells that express the ACE2 as the CoVID-19 receptor for its binding, entry (activation of the viral spike glycoprotein and ACE2 C-terminal segment cleavage), replication, and shedding. Epigenetics surveys have suggested that the ACE2 gene located on the X chromosome is regulated by DNA methylation 41-43. It was postulated that the variability in D/I genotype distribution of the ACE gene is possibly associated with the variable prevalence of the COVID-19 infection 42.
Notably, methylation varies across tissue cell types, and at three CpGs (cg04013915, cg08559914, and cg03536816) was lowest in lung epithelial cells. This figure was significantly lower among females than males, which differs in the ACE2 gene and protein expression and COVID-19 severity 44. Interestingly, increased ACE2 expression has been observed by staining lung tissue sections from patients with pulmonary hypertension. As the potential cause of ACE2 gene expression, enzymes that modify histones (KDM5B, H3K27a, H3K4me1, and H3K4me3) are notable. However, significant differences in ACE2 between racial groups, age groups, or gender groups were not verified in one study. Besides, smoking as an epigenome effector was not shown to have a role in COVID-19 infection risk. Also, IL-6 and INS (encoding the insulin hormone) genes have been associated with significant comorbidities. NAD-dependent histone deacetylase Sirtuin 1 (SIRT1) can also epigenetically induce the ACE gene expression under stress conditions. Viral infections cause a defect in the DNA methylation in lupus disease, causing further ACE2 gene hypomethylation and overexpression, leading to viral binding and cytokine storm and tissue damage COVID-19 infection 45, 46. The viral proteins exploit the host's genetic and epigenetic mediators, leading to viral evasion and determining disease pathophysiology (table1 and figure1). Besides, RAB1A gene was adequate for the COVID-19 infection development. Considering the ACE gene diffential expression, the age and sex of patients are also considered as risk factors for the COVID-19 infection 47.

Host and viral microRNAs epigenetic regulations
It has been revealed that epigenetics aspects of miRNA (small ncRNA molecules) mediated interactions with the host cells differ between SARSE-Cov and SARSE-Cov-2 (COVID-19). Hence, some viral miRNAs in a particular way affect several immune signaling pathways (IFN-I signaling, autophagy, etc.) that facilitate the prolonged latency. Moreover, COVID-19 modulates several critical cellular pathways resulting in the enhancement of anomalies in patients with comorbidities. The nucleocapsid protein from Coronavirus strain OC43 interacts with miR-9 and stimulates the NF-κB pathway. These findings are advantageous towards designing RNA therapeutics to mitigate the COVID-19 mediated comorbidities. Viral respiratory infections imposed by coronaviruses, influenza, adenovirus, rhinovirus, and RSV causes aberrant host miRNA expression mostly related to suppressing immune responses. Evidence has supposed that SARSE-Cov and SARSE-Cov-2 employ novel immune evasion strategies through utilizing host miRNA, but the exact mechanisms exerted by miRNA on the epigenetic interactions with the host have not been verified. It was hypothesized that genetic differences between SARSE-Cov and SARSE-Cov-2 and variations in binding to host miRNAs lead to differential pathogenesis 46.
Additionally, viral miRNAs differences and the fast mutation rate of SARSE-Cov2 in various regions have caused a higher pathogenicity rate. It was outlined that hsa-miR-20b-5p, hsa-miR-17-5p, and hsa-miR-323a-5p had anti-COVID-19 activities primarily targeting viral ORF1ab and S regions 44, 48. It is noteworthy that host miRNAs play a role like a double-edged sword and sometimes promote viral evasion, attachment, and replication. Patients suffering from underlying diseases (such as diabetes, cardiovascular diseases, and renal impairments) are more susceptible to SARS-CoV-2. It was revealed that host miRNA-mediated downregulated pathways disturb patients with the infection, making them more susceptible.
Viruses inflicting severe pulmonary illness can use three epigenetic-regulated approaches in the course of host-pathogen interaction: i. they execute affect host DNA methylation signatures then miRNAs regulating a cassette of genes underlying native yet adaptive antiviral responses; ii. those can encode because viral proteins up to expectation at once interact along with the host modified histones. Yet, iii. that may manipulate the host miRNA technology nuclear equipment in imitation of encoding viral non-canonical miRNA-like RNA fragments (v-miRNAs) regulating the viral life cycle or immune response 49. Here, we center on epigenetic-sensitive mechanisms via who H5N1 and SARS-CoV-2 can also affect susceptibility in imitation of pulmonary sickness by interfering with both born yet adaptive immune responses into human beings, as shown in Figure 2. 50, 51.


 
Figure 2. Viral–host epigenetic interactions. We illustrated that III putative cell-specific epigenetic-sensitive mechanisms using SARS-CoV-2 or H5N1 might also affect single sensitiveness according to severe pulmonary quintessential illness.

Mainly, T cells yet neutrophils execute bear deoxyribonucleic acid hypomethylation yet histone modifications, respectively, in COVID-19 patients. Otherwise, in vitro lung epithelial cells above H5N1 contamination can undergo adjustments of micro-ribonucleic sour taste (RNA) patterns yet histone tail marks, propulsion according to downregulation regarding antiviral defense. ACE, angiotensin-converting enzyme; AGO2, argonaute 2; CGI, CpG island; COVID-19, coronavirus disorder 2019; mRNA, messenger RNA; NET, neutrophil extracellular trap; NS1, non-structural protein 1; PCBP2, poly (RC)-binding protein 2; ROS, reactive oxygen species; SARS-CoV-2, severe acute respiratory indication coronavirus 2; SLE, systemic lupus erythematosus.

Patients'behavior, nutrition, and metabolic conditions
COVID19 patient's metabolic states determine the infection severity. Noticeably, ten human proteins, including SGTA, SPECC1, PHB, BCL2L1, FGL2, STAT3, JUN, PPP1CA, CAV1, and XPO1 interact with the SARSE-CoV-2. Interactions between SARSCoV's spike protein with lipid-rich membrane compartments and epigenetic modulations are considered targets to inhibit the viral infection 52. It was revealed that obesity is a risk factor for the SARSE-CoV-2 infection 53. Noticeably, ten human metabolic proteins, including SGTA, SPECC1, PHB, BCL2L1, FGL2, STAT3, JUN, PPP1CA, CAV1, and XPO1 interact with the SARSE-CoV-2. Interactions between SARSCoV's spike proteins, which have membranes rich in lipids components and epigenetic modulations, are considered targets to inhibit the viral infection. Some personal behaviors such as smoking or common personal behaviors that can reduce COVID-19 exposure are also notable, affecting the transmission, morbidity, and mortality rate 54, 55.

Future perspectives
Owing to the lack of effective vaccination until now, investigations in this regard will be promising. Additionally, the application of lower toxic disinfectants and adherence to personal hygiene; particularly among individuals meeting healthcare and developing effective drugs, can be helpful towards reducing the burden of infection. More in-depth verifications regarding epigenetic factors and application inhibitors of the ACE and outcomes are also proposed
 
CONCLUSION

Those epigenetic factors mainly facilitating the viral attachment to host cells seem to enhance the death rate. These primarily include methylation or expression of angiotensin-converting enzyme 2 (ACE2), microRNAs regulation, metabolic conditions, individual behavior (such as smoking), and some environmental conditions (temperature and humidity). The angiotensin-converting enzyme (ACE) is a significant receptor for SARS-CoV-2, which significantly expresses higher among individuals with comorbidities and under stress conditions. Patients with systemic lupus erythematosus are also prone to be susceptible to the disease. Viral infections cause a defect in the DNA methylation in lupus, causing further ACE2 hypomethylation and overexpression, leading to viral binding and also cytokine storm and tissue damage during COVID-19 infection. The microRNAs (miRNAs) epigenetics regulations also play a critical role in the suppression of immune responses.
Meanwhile, viral proteins interplays with the host cell are conferred mainly through TGF-β and HIF-1 signaling, endocytosis, autophagy, and Toll-like receptor signaling RIG-I signaling, Il-17 signaling, and fatty acid oxidation/degradation. Furthermore, the COVID19 patient's metabolic states determine the infection severity. Noticeably, ten human metabolic proteins, including SGTA, SPECC1, PHB, BCL2L1, FGL2, STAT3, JUN, PPP1CA, CAV1, and XPO1 interact with the SARSE-CoV-2. Interactions between SARSCoV's spike structural proteins containing membranes rich in lipidic macromolecules and epigenetic modulations are considered targets to inhibit the viral infection. Therefore, it seems that epigenetics plays a substantial role in the COVID-19 severity. Future in-depth studies will be promising. Vaccine design, particularly regarding ACE viral receptor monoclonal antibodies, is a proposal alongside adhering to personal hygiene.

Conflict of interest
None to declare
Acknowledgments
The authors wrote this study.

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Received: 24 January  2021
Accepted: 12 March 2021
Ahmed A Mhawesh1, Daniah Muneam Hamid2, Abdolmajid Ghasemian3
1Dept. of Med. and Mol. Biotech., College of Biotechnology, Alnahrain Univesirt, Baghdad, Iraq
2DNA Forensic center for research and training, Alnahrain University, Baghdad, Iraq
3 Islamic Azad University, Central Tehran Branch/Tehran/Iran
Corresponding author: alshammariahmed.a.m@gmail.com
1 Orcid ID: https://orcid.org/0000-0003-4546-7264
2 https://orcid.org/0000-0001-5539-3399
3 https://orcid.org/0000-0002-1243-6341
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