Coronavirus Disease 19 and Future Ecological Crises: Hopes from Epigenomics and Unraveling Genome Regulation in Humans and Infectious Agents

Abstract

With coronavirus disease 19 (COVID-19), we have witnessed a shift from public health to planetary health and a growing recognition of the importance of systems science in developing effective solutions against pandemics in the 21st century. COVID-19 and the history of frequent infectious outbreaks in the last two decades suggest that COVID-19 is likely a dry run for future ecological crises. Now is the right time to plan ahead and deploy the armamentarium of systems science scholarship for planetary health. The science of epigenomics, which investigates both genetic and nongenetic traits regarding heritable phenotypic alterations, and new approaches to understanding genome regulation in humans and pathogens offer veritable prospects to boost the global scientific capacities to innovate therapeutics and diagnostics against novel and existing infectious agents. Several reversible epigenetic alterations, such as chromatin remodeling and histone methylation, control and influence gene expression. COVID-19 lethality is linked, in part, to the cytokine storm, age, and status of the immune system in a given person. Additionally, due to reduced human mobility and daily activities, effects of the pandemic on the environment have been both positive and negative. For example, reduction in environmental pollution and lesser extraction from nature have potential positive corollaries on water and air quality. Negative effects include pollution as plastics and other materials were disposed in unconventional places and spaces in the course of the pandemic. I discuss the opportunities and challenges associated with the science of epigenomics, specifically with an eye to inform and prevent future ecological crises and pandemics that are looming on the horizon in the 21st century. In particular, this article underscores that epigenetics of both viruses and the host may influence virus infectivity and severity of attendant disease.

Introduction

The World Health Organization identified the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus disease 19 (COVID-19) in December 2019, with a pandemic declared in March 2021. The origins and root causes of the pandemic are being actively researched by the public health community worldwide (Andrew et al., 1982; Whitworth, 2020). As of February 23, 2021, the worldwide COVID-19 statistics put the number of cases as above 111 million with above 2 million deaths (Dong et al., 2020). SARS-CoV-2 derived its name from having a genome similar to SARS-CoV when sequenced (Qing and Gallagher, 2020; Zhu et al., 2020).

Several pieces of evidence link the SARS-CoV being transmitted from animals such as bats or pangolins to humans, with investigations still continuing at the time of writing this article (Benvenuto et al., 2020; Lu et al., 2020; Lvov and Alkhovsky, 2020). Although there have been two previous epidemics associated with SARS-CoV, COVID-19 is associated with more severe cases and symptoms, including shortness of breath, fever, severe pneumonia, acute respiratory distress syndrome, and organ failure (Guan et al., 2020; Li et al., 2020). The severity of the disease appears to be linked to age and comorbidities such as hypertension, diabetes, and obesity (Apea et al., 2021; Guan et al., 2020; Li et al., 2020; Suleyman et al., 2020).

Importantly, several reports indicate that individuals above 60 years of age are disproportionately affected by COVID-19 (Lithander et al., 2020; Salimi and Hamlyn, 2020). Reports indicate that aging is associated with slow metabolism, slow immune response to infections, and changes in cell and tissue architecture, leading to alterations in the functions of many biological systems (Bajaj et al., 2020; López-Otín et al., 2013; Weyand and Goronzy, 2016). As has been noted with cancer-causing mutations, age-linked genomic instability results in many chromosomal and epigenetic aberrations and mutations, leading to malfunctioning cellular systems impacting the immune system (Berdasco and Esteller, 2012; Fraga and Esteller, 2007; Gonzalo, 2010; Issa, 2003). Reports indicate ineffective viral clearance in an aged immune system, leading to disease fatalities (Bordallo et al., 2020; Mueller et al., 2020).

In young people, the youthful immune system responds to the viral infection in a much controlled manner compared with the aged immune system in the elderly (Covino et al., 2021; Mueller et al., 2020). A slow and ineffective immune response has great consequences in the case of a viral infection (Bansal et al., 2012; Oh et al., 2019; Tregoning and Schwarze, 2010). Reports indicate that consideration of the age factor during treatment of COVID-19 patients is reducing mortality in many countries (Cascella et al., 2020; Colaneri et al., 2020; Liu et al., 2020b; Vijayvargiya et al., 2020; Zhou et al., 2020a).

Coronaviruses: Cell Entry and Infection

Coronaviruses are small viruses of about 60–130 nm in diameter and belong to the Coronaviridae family within the Nidovirales order (McIntosh and Peiris, 2009; Saif et al., 2019). They are made of a single RNA strand with four subgroups, namely alpha (α), beta (β), gamma (γ), and delta (δ) (Hamid et al., 2020; Madabhavi et al., 2020; Shereen et al., 2020). SARS-CoV-2, the virus that causes COVID-19, belongs to the β subgroup and has a genome of ∼30 kb length consisting of 10 open reading frames (Chen et al., 2020b; Kandeel et al., 2020).

Structurally, coronaviruses are made up of a membrane, envelope, nucleocapsid, and spike protein (Kandeel et al., 2020). To attach to host cells, the virus uses the spike protein and fuses with the cell membrane (Hulswit et al., 2016). Once the virus enters the respiratory system, it can attach to cells through the spike protein and then fuses with the cell membrane, allowing infection to occur (Fig. 1) (Qing and Gallagher, 2020; Tortorici and Veesler, 2019; Walls et al., 2017).

FIG. 1.

The binding and entry of the SARS-CoV-2 virus into host cells. The spike protein binds to the receptor referred to as ACE2, allowing the viral RNA to enter the cell. After translation of viral proteins, assembly occurs in the endoplasmic reticulum–Golgi intermediate compartment. Through exocytosis, virions are then released. ACE2, angiotensin-converting enzyme 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

The spike protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in several cells, including lung, immune, testis, and endothelial cells (Letko et al., 2020; Wang et al., 2020b). Several host factors, including furin and other proteases, are involved in the entry of coronavirus into the cell (Hoffmann et al., 2020; Letko et al., 2020; Walls et al., 2020). Once inside the host cell, the coronavirus genome multiplies, and the host's ribosomes are involved in protein synthesis, with the virion assembled in the host's endoplasmic reticulum–Golgi intermediate complex (Hoffmann et al., 2020; Walls et al., 2020). The final virus is packaged into vesicles for cellular secretion (Li et al., 2005). Several reports indicate that SARS-CoV-2 can interact with receptors besides ACE2 and this requires further investigation (Strollo and Pozzilli, 2020; Vankadari and Wilce, 2020).

Epigenetics

The field of epigenetics covers investigations into heritable phenotypes that are stable and caused by conformational changes of the chromatin as well as activation states that do not result in changes in primary DNA nucleotide sequences (Berger et al., 2009; Dzobo, 2019). The study of genome epigenetics, also referred to as epigenomics, allows scientists to study and interpret the functions of epigenetic patterns and consequences of epigenetic alterations of the genome (D'Urso and Brickner, 2014; Falahi et al., 2015; Furukawa and Kikuchi, 2016; Jones et al., 2015; Pal and Tyler, 2016).

Recent data indicate that epigenetics plays a huge part in the initiation and progression of many diseases, including cancer and infectious diseases (Dzobo, 2019; Falahi et al., 2015; Fraga and Esteller, 2007; Furukawa and Kikuchi, 2016; Gonzalo, 2010; Jin and Liu, 2018). In addition, epigenetic marks made during early developmental stages influence gene expression as well as susceptibility to certain pathological conditions later in life (Gibney and Nolan, 2010; Nafee et al., 2008; Schäfer and Baric, 2017).

Unlike mutations, epigenetic alterations only affect chromatin conformation without changing the DNA, allowing epigenetic changes to be reversed and fast-acting in response to insults and microenvironmental changes (Goldberg et al., 2007; Jenuwein and Allis, 2001; Kouzarides, 2007). New data demonstrate real associations between epigenetics and cellular processes, including metabolism (Dimmeler et al., 2015; Keating and El-Osta, 2015; Keating et al., 2016; Miao et al., 2014). Methylation of DNA as well as modifications of histones results in chromatin changes that act in tandem with noncoding RNA, allowing proteins that regulate transcription to have access to the chromatin (Jaenisch and Bird, 2003; Wu and Zhang, 2014). By influencing transcription, epigenetic alterations impact protein synthesis (Ilango et al., 2020; Nöthling et al., 2020; Zhao et al., 2010). At any given time, activation states of chromatin influence a cell epigenome (The ENCODE Project Consortium, 2012).

Several enzymes are involved in epigenetic regulation and these include histone deacetylases (HDACs), histone methyltransferases, histone kinases, and histone acetyltransferases (Lin and Dent, 2006; Marmorstein and Trievel, 2009; Seto and Yoshida, 2014). Histone-modifying enzymes establish patterns that cause various proteins linked to the chromatin to have different affinities for each other and therefore contrasting and synergistic interactions (Biel et al., 2005; Eberharter and Becker, 2002; Keppler and Archer, 2008). These interactions determine whether the chromatin is in an active or silent state (Bannister and Kouzarides, 2011; Kouzarides, 2007; Strahl and Allis, 2000). Noncoding RNAs, lacking protein coding ability, have the ability to silence and activate gene expression through mimicking binding sites of transcription factors (Beermann et al., 2016; Boon et al., 2016; De Majo and Calore, 2018).

Viral Infection and Epigenetic Alterations

Identifying epigenetic alterations that cause and present in pathophysiological conditions allows scientists to develop new treatment strategies for different diseases. This can be achieved through combination therapies or by simply strengthening the immune system to fight off bacterial and viral infections (Bennett et al., 2020; Smale et al., 2014). Reports indicate that some viruses may not be able to integrate into the host DNA, but rather use the host's cellular machinery, including epigenetic mechanisms, to multiply and spread (Kennedy et al., 2015; Lieberman, 2016; Singh and Tscharke, 2020). The H3N2 influenza virus was shown to suppress the activation of the host's innate immune system by influencing epigenetic regulation of gene expression (Marazzi and Garcia-Sastre, 2015).

Other viruses such as hepatitis C virus as well as adenoviruses interfere with the host's epigenetic machinery and influence immune function (Ferrari et al., 2014; Seo et al., 2015). An association has been noted between influenza A virus and Middle East respiratory syndrome coronavirus (MERS-CoV) virus infection-mediated repressive histone modification with reduced expression of genes stimulated by interferon (IFN) despite activation by several transcription factors (Menachery et al., 2014). DNA methylation also results in reduced levels of antigen presentation molecules following MERS-CoV infection (Menachery et al., 2018). Through the use of latest sequencing techniques, it is possible to investigate the epigenetics of the whole genome. Reports indicate that viruses counteract the immune system through various epigenetic mechanisms.

Viruses such as SARS-CoV have the ability to switch off recognition by the immune system through encoding unique proteins (Liang et al., 2009; Schäfer and Baric, 2017). IFNs, necessary for antivirus response, have been shown to be regulated by epigenetic marks and the development of host response memory is linked to the epigenetic machinery (Fang et al., 2012; García-Sastre and Biron, 2006). Several reports have shown epigenetic regulation of innate immune response induction (Kaikkonen et al., 2011). In addition, increased H3K27me3 levels at promoter regions of IFN-stimulated genes have been associated with MERS-CoV infection, implying that viruses can target the innate immune response triggered by IFN (Menachery et al., 2014).

RNA modifications have also been linked to viruses such as SARS-CoV. Modifications of N6-methyladenosine play critical roles during viral replication (Kennedy et al., 2016; Lichinchi et al., 2016). In addition, methylation of RNAs of viruses may be directed at specific sequences only (Aevermann et al., 2014; Kaikkonen et al., 2011). Overall, viral infection, including SARS-CoV-2 infection, alters the epigenetic make-up of the host and, in turn, these epigenetic changes either promote or suppress viral replication and spread.

SARS-CoV-2 Infection and Epigenetics

New technologies have allowed the field of epigenetics to change within a short period of time, with novel data revealing how epigenetic marks play a huge role in memory and behavior and during development. It is obvious today that epigenetics is important in many facets of human life as well as in diseases (Obata et al., 2015; Portela and Esteller, 2010). In most cases, new data revealed that viruses can develop properties and functions that interfere with the host's epigenome and the genome to create an environment conducive for virus survival (Busslinger and Tarakhovsky, 2014; Vavougios, 2020).

In addition, recent reports indicate that mutations and chromatin changes during the process of aging alter the immune landscape in an individual, impacting the ability to respond to viral infections (López-Otín et al., 2013; Mueller et al., 2020). Already viruses related to SARS-CoV-2 have been shown to cause epigenetic changes by interfering with the host's activation of IFN response genes as well as influencing the host's antigen presentation (Islam et al., 2021; Liang et al., 2009). Studies on the methylation states of immune cells during and after infection are shedding new light on how virus infection impacts the host epigenetic landscape, and vice versa (Chen et al., 2020a; Domovitz and Gal-Tanamy, 2021).

The reason why SARS-CoV-2 infection can be severe in adults has to do with many factors, including the aged epigenome. Recent success in the development of vaccines against SARS-CoV-2 has raised hopes that the effects of the pandemic on day-to-day lives of people can soon be minimized. Most vaccines developed so far appear to work on various strains available and thus are able to elicit broadly neutralizing antibodies in vaccinated individuals (Brouwer et al., 2020; Erasmus et al., 2020; Rogers et al., 2020). The vaccines may also elicit T cell responses (Erasmus et al., 2020; Grifoni et al., 2020). Beside vaccines, several drugs are under investigation for their effectiveness against SARS-CoV-2 (Table 1).

Table 1.

Antiviral Drugs Under Investigation for Their Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2

Drug name	Clinical trial identifier
Lopinavir	NCT04386876
Lopinavir + hydroxychloroquine	NCT04328285
Umifenovir	NCT04476719
Favipiravir	NCT04336904
Convalescent plasma	NCT04321421
Mesenchymal stem cell (MSC)-derived exosomes	NCT04276987
Chinese medicine + vitamin	NCT03680274
Decitabine	NCT04482621

Combination therapy with antiviral drugs and epigenetic-targeted drugs is gaining ground in the search for successful treatment of SARS-CoV-2. These strategies may inhibit viral entry and replication as well as boost the host's immune response (El Baba and Herbein, 2020; Sang et al., 2021). Currently, several drugs targeting the epigenome have been shown to be useful in reducing the severity of COVID-19 and some have been approved by the Food and Drug Administration (FDA) (Atlante et al., 2020; Dandara et al., 2020; Dzobo et al., 2021; Zhou et al., 2020b). Therapies that specifically target the SARS-CoV-2 virus can do so through inhibiting viral replication and virus–receptor binding. Several enzymes necessary for viral replication, including proteases, can be inhibited by drugs such as galidesivir and darunavir.

Other broad-acting drugs can also suppress virus infection. Valproic acid has been shown to have antiviral activity (Gordon et al., 2020). Trichostatin A together with rapamycin and other antiviral agents has been shown to downregulate proinflammatory mediator production (Adhikari et al., 2020). Panobinostat and belinostat are HDAC inhibitors shown to affect several signaling pathways necessary for viral replication and survival, including the transforming growth factor-β cascade (Dejligbjerg et al., 2008; Patnaik and Anupriya, 2019).

Properties of antiviral agents such as pharmacokinetics are impacted by epigenetic regulation, placing epigenetics at the center of drug discovery and treatment of SARS-CoV-2 (Barnabas et al., 2020; Paniri et al., 2020). Several epigenetic mechanisms and networks involved in SARS-CoV-2 infection have been revealed and these are under investigation (El Baba and Herbein, 2020; Sang et al., 2021). HDACs have been shown to regulate several proteins involved in viral multiplication and maturation (Nehme et al., 2019). As a result, many drugs and compounds that can abrogate the effects of HDACs have shown effectiveness at slowing infection and preventing severe cases of COVID-19 (Cole et al., 2016; Pascual, 2020; Wang et al., 2020a).

In addition, the expression of ACE2, the receptor through which SARS-CoV-2 attaches to cells, has been shown to be controlled partly by DNA methylation and modifications of histones, meaning enzymes such as HDACs and acetyltransferases are targets to modulate the host's immune response to viral infection (Chai et al., 2020; Chlamydas et al., 2020). Investigations are therefore underway to evaluate the effectiveness of valproic acid and azacitidine against SARS-CoV-2 infection (Chlamydas et al., 2020). Azacitidine can be used against SARS-CoV-2 and act through viral mimicry (Li and De Clercq, 2020). Several inhibitors of bromodomain and extra-terminal (BET) proteins, including CPI-0610 and ABBV-744, act by boosting the immune response to viral infection as well as blocking viral attachment to human cells (Zhang and Kuchroo, 2019).

Furthermore, epigenetic drugs currently in use for cancer are being investigated for their effectiveness in the treatment of COVID-19. This is partly because most epigenetic drugs regulate cellular processes such as inflammation and the immune system (Pruimboom, 2020; van Dam et al., 2020). Investigations reveal that the cytokine storm is linked to severe cases of COVID-19, linking production of cytokines with adverse outcomes (Dzobo et al., 2021; Hamid et al., 2020; Hoffmann et al., 2020). Therapeutic agents that inhibit inflammation are therefore appealing in the treatment of COVID-19.

Several studies have shown that immune cells can maintain a memory of past infection events through epigenetic mechanisms (Kerboua, 2020; Netea et al., 2020). This so-called trained immunity appears to be useful in reducing the severity of COVID-19 and can be broad-based immunity against variants of the virus (Netea et al., 2020). Exposure to an insult leads to many changes, including epigenetic reprogramming, resulting in some memory, which can lead to an increased immune response in case the exposure occurs again (Geller and Yan, 2020).

Furthermore, natural products have been suggested to act in reprogramming the epigenome and ultimately improve the immune response to infections (Fang et al., 2020; Singh, 2020; Thomford et al., 2018; Vyas et al., 2020). Importantly, reports indicate that vitamin D can reduce the severity of COVID-19 potentially through suppressing inflammation and the cytokine storm (Allegra et al., 2020; Ferder et al., 2020; Pruimboom, 2020; Singh, 2020).

Advances in technologies and the deposition of data within publicly available databases have allowed scientists to work much faster in terms of coming up with solutions for prevailing diseases. Currently, it is possible to obtain epigenomic data of individuals very fast and interpretation can be aided through the use of artificial intelligence (Dzobo, 2019; Dzobo et al., 2019). By combining both genomic and epigenomic data, scientists are able to diagnose the disease and apply personalized and targeted treatment at times (Rabouw et al., 2016; Thomford et al., 2019; Thornbrough et al., 2016).

COVID-19 Pandemic Effects on the Environment

With climate change and other socioecological events taking place on earth, the stability of systems on earth is put to the test. Science must help the earth survive through coming up with early prediction systems and ways to respond to natural disasters, for example. In March of 2020, the World Health Organization declared COVID-19 a pandemic and the disease provided great challenges for humanity by incapacitating health care systems (Cucinotta and Vanelli, 2020; Ferretti et al., 2020). Huge advances have been made in monitoring of disease spread, communication and transmission of data, biomedical sciences, and artificial intelligence and these have resulted in increased quality of life (Cornwall, 2020; Vokó and Pitter, 2020). Threats still exist in the form of nuclear proliferation, sliding backward democracies, and terrorist activities, making our disaster preparedness not up to standard.

The main reason that epidemic diseases start and spread is the interaction between humans and animals, from domesticated animals to wild animals (Cleaveland et al., 2001; Taylor et al., 2001; Woolhouse and Gowtage-Sequeria, 2005). Eating wild animal meat as well as living within close proximity of animals ultimately causes animal pathogens to be passed on to humans. The COVID-19 pandemic is widespread and has a range of impacts on the environment.

There has been a lot of interest on the spread of COVID-19 as well as its effects on socioecological systems, which include soil, climate, and water. The general conditions of the environment can help spread or inhibit the spread of the virus (Liu et al., 2020a; Xie and Zhu, 2020). For example, while it is not a treatment strategy, exposure of the virus to ultraviolet light results in its inactivation (Lytle and Sagripanti, 2005; Sagripanti and Lytle, 2007, 2020). However, warm temperature cannot stop the spread of the virus.

The COVID-19 pandemic caused many countries to shut down their economies or limit economic activity, thus impacting the environment. Reduced economic activities might result in increased poverty as well as reduced efforts to invest in long-term goals. On an individual level, many people had to adjust their lifestyles as well as interpersonal affairs (Balanzá-Martínez et al., 2020; Di Renzo et al., 2020). While outdoor crime decreased due to lockdowns, reports of increased domestic violence have been prevalent as people were kept in close proximity to each other (Das et al., 2020; Perez-Vincent et al., 2020; Roesch et al., 2020).

It is important that the old and fragile people in society are looked after with access to good health care facilities. It is obvious that the COVID-19 pandemic caused negative effects on the economy and society at large, but some of the consequences of the pandemic have seen the environment improve in terms of lack of pollution and improvement in water and air quality, for example. As an effect on the environment, pandemics can trigger migration from high-risk areas to low-risk or lockdown-free areas in the country or across countries (Chen et al., 2020c; Rothan and Byrareddy, 2020).

Many reports documented the improved air quality as the pandemic progressed (Czuba, 2020; Tollefson, 2020). Reduced air travel meant that greenhouse emissions were also reduced (Harrison et al., 2015; Kivits et al., 2010). Noise pollution was also decreased (Arora et al., 2020; Basu et al., 2021). On the negative side, reduced export of several products, including agricultural and fish products, meant that large amounts of organic waste were generated. In addition, it became difficult to monitor changes in the natural ecosystems (Barouki et al., 2021; Cooke et al., 2021).

For urban populations, focus was placed on the effect of the COVID-19 pandemic on mental health of individuals. This is partly due to the compact nature of cities, with people living in close proximity to each other. The rural populations tend to have more space between individuals. Recent reports show that SARS-CoV-2 can be detected in sewage, but there is no need for panic as the virus easily dies in water and can be inactivated by the warm water of sewage conditions (Ahmed et al., 2020; Gundy et al., 2009; Medema et al., 2020). The presence of SARS-CoV on surfaces will be one of the key factors to finally control its spread. Reports indicate that the virus remains on surfaces for many days (Nag et al., 2020; Van Doremalen et al., 2020). New and better methods of purifying water and air are required.

Overall, the impact of the COVID-19 pandemic has been enormous. Table 2 highlights important points relating to the intersection of epigenetics and pandemic prevention or response. From impacting people's movement to economic slowdown, the COVID-19 pandemic has both short- and long-term effects. In addition, the COVID-19 pandemic demonstrates the interconnectedness of human health and planetary well-being. Once the pandemic spread to all corners of the globe, lockdowns became an everyday thing, with consequences felt locally and globally.

Table 2.

Intersection of Epigenetics and Coronavirus Disease 19 Pandemic Prevention or Response

• SARS-CoV-2 infection must also be viewed from an epigenetic viewpoint with the potential to control gene expression to ameliorate effects of the infection.

• Epigenetic-specific drugs in combination with other antiviral drugs must be evaluated.

• Epigenetic-specific drugs can be used against the cytokine storm to reduce mortality.

• Investigate host–virus interactions in infection susceptibility and disease severity.

• Delineate epigenetic regulation involved in the cytokine storm associated with SARS-CoV-2.

• Human and planetary well-being is connected.

• Solutions for pandemics must be interdisciplinary.

• Early interventions in case of pandemics must include keeping track of socioecological systems.

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Conclusions

The COVID-19 disease was identified as a pandemic by the World Health Organization and has devastated many lives and economies worldwide. Given the challenges associated with a highly infectious disease, development of vaccines was accelerated and we now have several vaccines approved by the FDA and other regulatory agencies in various countries. Severe cases of COVID-19 are associated with a cytokine storm characterized by increased inflammation and release of large amounts of cytokines, including interleukin (IL)-6 and IL-18. This can easily lead to multiple organ damage and death. SARS-CoV-2 infection has been observed to be associated with various epigenetic alterations of the host's epigenome. Current studies are investigating epigenetic alterations and inhibitors with the hope of innovation for therapeutic agents or repurposing already existing drugs.

The science of epigenomics is poised to inform and prevent future ecological crises and pandemics that are looming on the horizon in the 21st century. In particular, epigenetics of both viruses and the host may influence virus infectivity and severity of attendant disease.

Footnotes

Author Disclosure Statement

The author declares there are no conflicting financial interests.

Funding Information

No funding was received in support of this study.

Abbreviations Used

References

Adhikari

, Meng

, Wu

Y-J

, et al. (2020). Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: A scoping review. Infect Dis poverty, 9, 1–12.

Aevermann

, Pickett

, Kumar

, et al. (2014). A comprehensive collection of systems biology data characterizing the host response to viral infection. Sci Data, 1, 1–21.

Ahmed

, Angel

, Edson

, et al. (2020). First confirmed detection of SARS-CoV-2 in untreated wastewater in Australia: A proof of concept for the wastewater surveillance of COVID-19 in the community. Sci Total Environ, 728, 138764.

Allegra

, Tonacci

, Pioggia

, Musolino

, and Gangemi

. (2020). Vitamin deficiency as risk factor for SARS-CoV-2 infection: Correlation with susceptibility and prognosis. Eur Rev Med Pharmacol Sci, 24, 9721–9738.

Andrew

, Kramer

, and Rawdon

. (1982). The embryonic origin of endocrine cells of the gastrointestinal tract. Gen Comp Endocrinol, 47, 249–265.

Apea

, Wan

, Dhairyawan

, et al. (2021). Ethnicity and outcomes in patients hospitalised with COVID-19 infection in East London: An observational cohort study. BMJ Open, 11, e042140.

Arora

, Bhaukhandi

, and Mishra

. (2020). Coronavirus lockdown helped the environment to bounce back. Sci Total Environ, 742, 140573.

Atlante

, Mongelli

, Barbi

, Martelli

, Farsetti

, and Gaetano

. (2020). The epigenetic implication in coronavirus infection and therapy. Clin Epigenet, 12, 1–12.

Bajaj

, Gadi

, Spihlman

, Wu

, Choi

, and Moulton

. (2020). Aging, immunity, and COVID-19: How age influences the host immune response to coronavirus infections?. Front Physiol, 11, 571416.

10.

Balanzá-Martínez

, Atienza–Carbonell

, Kapczinski

, and De Boni

. (2020). Lifestyle behaviours during the COVID-19–time to connect. Acta Psychiatr Scand, 141, 399–400.

11.

Bannister

, and Kouzarides

. (2011). Regulation of chromatin by histone modifications. Cell Res, 21, 381–395.

12.

Bansal

, Bradley

, Bishop

, Kiani-Alikhan

, and Ford

. (2012). Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immunity, 26, 24–31.

13.

Barnabas

, Brown

, Bershteyn

, et al. (2020). Efficacy of hydroxychloroquine for post-exposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among adults exposed to coronavirus disease (COVID-19): A structured summary of a study protocol for a randomised controlled trial. Trials, 21, 475.

14.

Barouki

, Kogevinas

, Audouze

, et al. (2021). The COVID-19 pandemic and global environmental change: Emerging research needs. Environ Int, 146, 106272.

15.

Basu

, Murphy

, Molter

, et al. (2021). Investigating changes in noise pollution due to the COVID-19 lockdown: The case of Dublin, Ireland. Sustain Cities Soc, 65, 102597.

16.

Beermann

, Piccoli

M-T

, Viereck

, and Thum

. (2016). Non-coding RNAs in development and disease: Background, mechanisms, and therapeutic approaches. Physiol Rev, 96, 1297–1325.

17.

Bennett

, Troutman

, Sakai

, and Glass

. (2020). Epigenetic regulation of Kupffer cell function in health and disease. Front Immunol, 11, 609618.

18.

Benvenuto

, Giovanetti

, Ciccozzi

, Spoto

, Angeletti

, and Ciccozzi

. (2020). The 2019-new coronavirus epidemic: Evidence for virus evolution. J Med Virol, 92, 455–459.

19.

Berdasco

, and Esteller

. (2012). Hot topics in epigenetic mechanisms of aging: 2011. Aging Cell, 11, 181–186.

20.

Berger

, Kouzarides

, Shiekhattar

, and Shilatifard

. (2009). An operational definition of epigenetics. Genes Dev, 23, 781–783.

21.

Biel

, Wascholowski

, and Giannis

. (2005). Epigenetics—an epicenter of gene regulation: Histones and histone-modifying enzymes. Angew Chem Int Ed, 44, 3186–3216.

22.

Boon

, Jaé

, Holdt

, and Dimmeler

. (2016). Long noncoding RNAs: From clinical genetics to therapeutic targets?. J Am Coll Cardiol, 67, 1214–1226.

23.

Bordallo

, Bellas

, Cortez

, Vieira

, and Pinheiro

. (2020). Severe COVID-19: What have we learned with the immunopathogenesis?. Adv Rheumatol, 60, 50.

24.

Brouwer

, Caniels

, Van Der Straten

, et al. (2020). Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science, 369, 643–650.

25.

Busslinger

, and Tarakhovsky

. (2014). Epigenetic control of immunity. Cold Spring Harb Perspect Biol, 6, a019307.

26.

Cascella

, Rajnik

, Cuomo

, Dulebohn

, and Di Napoli

. (2020). Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls(Internet). Treasure Island, FL: StatPearls. Publishing.

27.

Chai

, Yu

, Ge

, Jia

, and Fan

. (2020). Genetic alteration, RNA expression, and DNA methylation profiling of coronavirus disease 2019 (COVID-19) receptor ACE2 in malignancies: A pan-cancer analysis. J Hematol Oncol, 13, 1–5.

28.

Chen

, Wang

, Liu

, et al. (2020a). Targeting the histone methyltransferase disruptor of telomeric silencing 1-like restricts avian leukosis virus subgroup J replication by restoring the innate immune response in chicken macrophages. Front Microbiol, 11, 603131.

29.

Chen

, Liu

, and Guo

. (2020b). Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol, 92, 418–423.

30.

Chen

Z-L

, Zhang

, Lu

, et al. (2020c). Distribution of the COVID-19 epidemic and correlation with population emigration from Wuhan, China. Chin Med J, 133, 1044–1050.

31.

Chlamydas

, Papavassiliou

, and Piperi

. (2020). Epigenetic mechanisms regulating COVID-19 infection. Epigenetics, 16, 263–270.

32.

Cleaveland

, Laurenson

, and Taylor

. (2001). Diseases of humans and their domestic mammals: Pathogen characteristics, host range and the risk of emergence. Philos Trans R Soc Lond Ser B Biol Sci, 356, 991–999.

33.

Colaneri

, Bogliolo

, Valsecchi

, et al. (2020). Tocilizumab for treatment of severe COVID-19 patients: Preliminary results from SMAtteo COvid19 REgistry (SMACORE). Microorganisms, 8, 695.

34.

Cole

, Morris

, Dickman

, and Dockrell

. (2016). The therapeutic potential of epigenetic manipulation during infectious diseases. Pharmacol Ther, 167, 85–99.

35.

Cooke

, Twardek

, Lynch

, et al. (2021). A global perspective on the influence of the COVID-19 pandemic on freshwater fish biodiversity. Biol Conserv, 253, 108932.

36.

Cornwall

. (2020). Can you put a price on COVID-19 options? Experts weigh lives versus economics. Science. 10.

37.

Covino

, De Matteis

, Polla

DaD

, et al. (2021). Predictors of in-hospital mortality and death risk stratification among COVID-19 patients aged ≥80 years old. Arch Gerontol Geriatr, 95, 104383.

38.

Cucinotta

, and Vanelli

. (2020). WHO declares COVID-19 a pandemic. Acta Biomed, 91, 157–160.

39.

Czuba

. (2020). Opportunities and challenges for shaping ecological safety in the times of the coronavirus pandemic. The European perspective. Earth, 11, 48.

40.

D'urso

, and Brickner

. (2014). Mechanisms of epigenetic memory. Trends Genet, 30, 230–236.

41.

Dandara

, Dzobo

, and Chirikure

. (2020). COVID-19 pandemic and Africa: From the situation in Zimbabwe to a case for precision herbal medicine. OMICS [Epub ahead of print]; DOI: 10.1089/omi.2020.0099.

42.

Das

, Das

, and Mandal

. (2020). Examining the impact of lockdown (due to COVID-19) on domestic violence (DV): An evidences from India. Asian J Psychiatry, 54, 102335.

43.

De Majo

, and Calore

. (2018). Chromatin remodelling and epigenetic state regulation by non-coding RNAs in the diseased heart. Noncoding RNA Res, 3, 20–28.

44.

Dejligbjerg

, Grauslund

, Litman

, et al. (2008). Differential effects of class I isoform histone deacetylase depletion and enzymatic inhibition by belinostat or valproic acid in HeLa cells. Mol Cancer, 7, 70.

45.

Di Renzo

, Gualtieri

, Pivari

, et al. (2020). Eating habits and lifestyle changes during COVID-19 lockdown: An Italian survey. J Transl Med, 18, 1–15.

46.

Dimmeler

, Marian

, and Olson

. (2015). Epigenetics and metabolism. Circ Res 2015;116:715–736.

47.

Domovitz

, and Gal-Tanamy

. (2021). Tracking down the epigenetic footprint of HCV-induced hepatocarcinogenesis. J Clin Med, 10, 551.

48.

Dong

, Du

, and Gardner

. (2020). An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis, 20, 533–534.

49.

Dzobo

. (2019). Epigenomics-guided drug development: Recent advances in solving the cancer treatment “jigsaw puzzle”. OMICS, 23, 70–85.

50.

Dzobo

, Adotey

, Thomford

, and Dzobo

. (2019). Integrating artificial and human intelligence: A partnership for responsible innovation in biomedical engineering and medicine. OMICS, 24, 247–263.

51.

Dzobo

, Chiririwa

, Dandara

, and Dzobo

. (2021). Coronavirus disease-2019 treatment strategies targeting interleukin-6 signaling and herbal medicine. OMICS, 25, 13–22.

52.

Eberharter

, and Becker

. (2002). Histone acetylation: A switch between repressive and permissive chromatin. EMBO Rep, 3, 224–229.

53.

El Baba

, and Herbein

. (2020). Management of epigenomic networks entailed in coronavirus infections and COVID-19. Clin Epigenet, 12, 1–12.

54.

Erasmus

, Khandhar

, O'connor

, et al. (2020). An alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates. Sci Transl Med, 12, eabc9396.

55.

Falahi

, Sgro

, and Blancafort

. (2015). Epigenome engineering in cancer: Fairytale or a realistic path to the clinic?. Front Oncol, 5, 22.

56.

Fang

, Schaefer

, Mecklenbrauker

, et al. (2012). Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response. J Exp Med, 209, 661–669.

57.

Fang

, Yang

, Yu

, et al. (2020). Natural products as LSD1 inhibitors for cancer therapy. Acta Pharm Sin B, 11, 621–631.

58.

Ferder

, Martín Giménez

, Inserra

, et al. (2020). Vitamin D supplementation as a rational pharmacological approach in the Covid-19 pandemic. Am J Physiol Lung Cell Mol Physiol, 319, L941–L948.

59.

Ferrari

, Gou

, Jawdekar

, et al. (2014). Adenovirus small E1A employs the lysine acetylases p300/CBP and tumor suppressor Rb to repress select host genes and promote productive virus infection. Cell Host Microbe, 16, 663–676.

60.

Ferretti

, Wymant

, Kendall

, et al. (2020). Quantifying SARS-CoV-2 transmission suggests epidemic control with digital contact tracing. Science, 368, eabb6936.

61.

Fraga

, and Esteller

. (2007). Epigenetics and aging: The targets and the marks. Trends Genet, 23, 413–418.

62.

Furukawa

, and Kikuchi

. (2016). Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma. Int J Hematol, 104, 281–292.

63.

García-Sastre

, and Biron

. (2006). Type 1 interferons and the virus-host relationship: A lesson in detente. Science, 312, 879–882.

64.

Geller

, and Yan

. (2020). Could the induction of trained immunity by β-glucan serve as a defense against COVID-19?. Front Immunol, 11, 1782.

65.

Gibney

, and Nolan

. (2010). Epigenetics and gene expression. Heredity, 105, 4–13.

66.

Goldberg

, Allis

, and Bernstein

. (2007). Epigenetics: A landscape takes shape. Cell, 128, 635–638.

67.

Gonzalo

. (2010). Epigenetic alterations in aging. J Appl Physiol, 109, 586–597.

68.

Gordon

, Jang

, Bouhaddou

, et al. (2020). A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature, 583, 459–468.

69.

Grifoni

, Weiskopf

, Ramirez

, et al. (2020). Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals. Cell, 181, 1489–1501.e15.

70.

Guan

, Liang

, He

, and Zhong

. (2020). Cardiovascular comorbidity and its impact on patients with COVID-19. Eur Respir J, 55, 2001227.

71.

Gundy

, Gerba

, and Pepper

. (2009). Survival of coronaviruses in water and wastewater. Food Environ Virol, 1, 10–14.

72.

Hamid

, Mir

, and Rohela

. (2020). Noval coronavirus disease (COVID-19): A pandemic (epidemiology, pathogenesis and potential therapeutics). New Microbes New Infect, 35, 100679.

73.

Harrison

, Masiol

, and Vardoulakis

. (2015). Civil aviation, air pollution and human health. Environ Res Lett, 10, 041001.

74.

Hoffmann

, Kleine-Weber

, Schroeder

, et al. (2020). SARS-CoV-2cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell, 181, 271–280.e8.

75.

Hulswit

, De Haan

, and Bosch

. (2016). Coronavirus spike protein and tropism changes. Adv Virus Res, 96, 29–57.

76.

Ilango

, Paital

, Jayachandran

, Padma

, and Nirmaladevi

. (2020). Epigenetic alterations in cancer. Front Biosci (Landmark Ed), 25, 1058–1109.

77.

Islam

, Khan

, Ahmed

, et al. (2021). Transcriptome of nasopharyngeal samples from COVID-19 patients and a comparative analysis with other SARS-CoV-2 infection models reveal disparate host responses against SARS-CoV-2. J Transl Med, 19, 32.

78.

Issa

J-P

. (2003). Age-related epigenetic changes and the immune system. Clin Immunol, 109, 103–108.

79.

Jaenisch

, and Bird

. (2003). Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet, 33, 245–254.

80.

Jenuwein

, and Allis

. (2001). Translating the histone code. Science, 293, 1074–1080.

81.

Jin

, and Liu

. (2018). DNA methylation in human diseases. Genes Dis, 5, 1–8.

82.

Jones

, Goodman

, and Kobor

. (2015). DNA methylation and healthy human aging. Aging Cell, 14, 924–932.

83.

Kaikkonen

, Lam

, and Glass

. (2011). Non-coding RNAs as regulators of gene expression and epigenetics. Cardiovasc Res, 90, 430–440.

84.

Kandeel

, Ibrahim

, Fayez

, and Al-Nazawi

. (2020). From SARS and MERS CoVs to SARS-CoV-2: Moving toward more biased codon usage in viral structural and nonstructural genes. J Med Virol, 92, 660–666.

85.

Keating

, and El-Osta

. (2015). Epigenetics and metabolism. Circ Res, 116, 715–736.

86.

Keating

, Plutzky

, and El-Osta

. (2016). Epigenetic changes in diabetes and cardiovascular risk. Circ Res, 118, 1706–1722.

87.

Kennedy

, Bogerd

, Kornepati

, et al. (2016). Posttranscriptional m(6)A editing of HIV-1 mRNAs enhances viral gene expression. Cell Host Microbe, 19, 675–685.

88.

Kennedy

, Rovnak

, Badani

, and Cohrs

. (2015). A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation. J Gen Virol, 96, 1581–1602.

89.

Keppler

, and Archer

. (2008). Chromatin-modifying enzymes as therapeutic targets—part 2. Expert Opin Ther Targets, 12, 1457–1467.

90.

Kerboua

. (2020). The perplexing question of trained immunity vs adaptive memory in COVID-19. J Med Virol, 92, 1858–1863.

91.

Kivits

, Charles

, and Ryan

. (2010). A post-carbon aviation future: Airports and the transition to a cleaner aviation sector. Futures, 42, 199–211.

92.

Kouzarides

. (2007). Chromatin modifications and their function. Cell, 128, 693–705.

93.

Letko

, Marzi

, and Munster

. (2020). Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol, 5, 562–569.

94.

, Yang

, Zhao

, et al. (2020). Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol, 109, 531–538.

95.

, and De Clercq

. (2020). Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov, 19, 149–150.

96.

, Zhang

, Sui

, et al. (2005). Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J, 24, 1634–1643.

97.

Liang

, Vogel

, Narayanan

, Peng

, and Kristie

. (2009). Inhibition of the histone demethylase LSD1 blocks α-herpesvirus lytic replication and reactivation from latency. Nat Med, 15, 1312–1317.

98.

Lichinchi

, Gao

, Saletore

, et al. (2016). Dynamics of the human and viral m(6)A RNA methylomes during HIV-1 infection of T cells. Nat Microbiol, 1, 16011.

99.

Lieberman

. (2016). Epigenetics and genetics of viral latency. Cell Host Microbe, 19, 619–628.

100.

Lin

, and Dent

. (2006). Functions of histone-modifying enzymes in development. Curr Opin Genet Dev, 16, 137–142.

101.

Lithander

, Neumann

, Tenison

, et al. (2020). COVID-19 in older people: A rapid clinical review. Age Ageing, 49, 501–515.

102.

Liu

, Zhou

, Yao

, et al. (2020a). Impact of meteorological factors on the COVID-19 transmission: A multi-city study in China. Sci Total Environ, 726, 138513.

103.

Liu

, Chen

, Lin

, and Han

. (2020b). Clinical features of COVID-19 in elderly patients: A comparison with young and middle-aged patients. J Infect, 80, e14–e18.

104.

López-Otín

, Blasco

, Partridge

, Serrano

, and Kroemer

. (2013). The hallmarks of aging. Cell, 153, 1194–1217.

105.

, Zhao

, Li

, et al. (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet, 395, 565–574.

106.

Lvov

, and Alkhovsky

. (2020). [Source of the COVID-19 pandemic: Ecology and genetics of coronaviruses (Betacoronavirus: Coronaviridae) SARS-CoV, SARS-CoV-2 (subgenus Sarbecovirus), and MERS-CoV (subgenus Merbecovirus).]. Vopr Virusol 65, 62–70 (Article in Russian).

107.

Lytle

, and Sagripanti

J-L

. (2005). Predicted inactivation of viruses of relevance to biodefense by solar radiation. J Virol, 79, 14244–14252.

108.

Madabhavi

, Sarkar

, and Kadakol

. (2020). COVID-19: A review. Monaldi Arch Chest Dis 90, [Epub ahead of print]; DOI: 10.4081/monaldi.2020.1298.

109.

Marazzi

, and Garcia-Sastre

. (2015). Interference of viral effector proteins with chromatin, transcription, and the epigenome. Curr Opin Microbiol, 26, 123–129.

110.

Marmorstein

, and Trievel

. (2009). Histone modifying enzymes: Structures, mechanisms, and specificities. Biochim Biophys Acta, 1789, 58–68.

111.

Mcintosh

, and Peiris

. (2009). Coronaviruses. I. Clinical Virology. 3rd edition. American Society of, Microbiology, 1155–1171.

112.

Medema

, Heijnen

, Elsinga

, Italiaander

, and Brouwer

. (2020). Presence of SARS-Coronavirus-2 RNA in sewage and correlation with reported COVID-19 prevalence in the early stage of the epidemic in the Netherlands. Environ Sci Technol Lett, 7, 511–516.

113.

Menachery

, Eisfeld

, Schäfer

, et al. (2014). Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses. mBio, 5, e01174-14.

114.

Menachery

, Schäfer

, Burnum-Johnson

, et al. (2018). MERS-CoV and H5N1 influenza virus antagonize antigen presentation by altering the epigenetic landscape. Proc Natl Acad Sci USA, 115, e1012–e1021.

115.

Miao

, Chen

, Genuth

, et al. (2014). Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes. Diabetes, 63, 1748–1762.

116.

Mueller

, Mcnamara

, and Sinclair

. (2020). Why does COVID-19 disproportionately affect older people?. Aging (Albany NY), 12, 9959.

117.

Nafee

, Farrell

, Carroll

, Fryer

, and Ismail

. (2008). Epigenetic control of fetal gene expression. BJOG, 115, 158–168.

118.

Nag

, Whyte

, Markey

, et al. (2020). Ranking hazards pertaining to human health concerns from land application of anaerobic digestate. Sci Total Environ, 710, 136297.

119.

Nehme

, Pasquereau

, and Herbein

. (2019). Control of viral infections by epigenetic-targeted therapy. Clin Epigenet, 11, 1–17.

120.

Netea

, Giamarellos-Bourboulis

, Domínguez-Andrés

, et al. (2020). Trained immunity: A tool for reducing susceptibility to and the severity of SARS-CoV-2 infection. Cell, 181, 969–977.

121.

Nöthling

, Malan-Müller

, Abrahams

, Hemmings

SMJ

, and Seedat

. (2020). Epigenetic alterations associated with childhood trauma and adult mental health outcomes: A systematic review. World J Biol Psychiatry, 21, 493–512.

122.

Obata

, Furusawa

, and Hase

. (2015). Epigenetic modifications of the immune system in health and disease. Immunol Cell Biol, 93, 226–232.

123.

S-J

, Lee

, and Shin

. (2019). Aging and the immune system: The impact of immunosenescence on viral infection, immunity and vaccine immunogenicity. Immune Netw, 19, e37.

124.

Pal

, and Tyler

. (2016). Epigenetics and aging. Sci Adv, 2, e1600584.

125.

Paniri

, Hosseini

, Rasoulinejad

, and Akhavan-Niaki

. (2020). Molecular effects and retinopathy induced by hydroxychloroquine during SARS-CoV-2 therapy: Role of CYP450 isoforms and epigenetic modulations. Eur J Pharmacol, 886, 173454.

126.

Pascual

. (2020). Coronavirus SARS-CoV-2: Analysis of subgenomic mRNA transcription, 3CLpro and PL2pro protease cleavage sites and protein synthesis. arXiv preprint arXiv:2004.00746.

127.

Patnaik

, and Anupriya . (2019). Drugs targeting epigenetic modifications and plausible therapeutic strategies against colorectal cancer. Front Pharmacol, 10, 588.

128.

Perez-Vincent

, Carreras

, Gibbons

, Murphy

, and Rossi

. (2020). COVID-19 Lockdowns and Domestic Violence. Washington, DC: Inter-American Development Bank.

129.

Portela

, and Esteller

. (2010). Epigenetic modifications and human disease. Nat Biotechnol, 28, 1057–1068.

130.

Pruimboom

. (2020). Methylation pathways and SARS-CoV-2 lung infiltration and cell membrane-virus fusion are both subject to epigenetics. Front Cell Infect Microbiol, 10, 290.

131.

Qing

, and Gallagher

. (2020). SARS coronavirus redux. Trends Immunol, 41, 271–273.

132.

Rabouw

, Langereis

, Knaap

, et al. (2016). Middle East respiratory coronavirus accessory protein 4a inhibits PKR-mediated antiviral stress responses. PLoS Pathog, 12, e1005982.

133.

Roesch

, Amin

, Gupta

, and García-Moreno

, (2020). Violence against women during covid-19 pandemic restrictions. BMJ 369, m1712.

134.

Rogers

, Zhao

, Huang

, et al. (2020). Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science, 369, 956–963.

135.

Rothan

, and Byrareddy

. (2020). The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun, 109, 102433.

136.

Sagripanti

, and Lytle

. (2007). Inactivation of influenza virus by solar radiation. Photochem Photobiol, 83, 1278–1282.

137.

Sagripanti

, and Lytle

. (2020). Estimated inactivation of coronaviruses by solar radiation with special reference to COVID-19. Photochem Photobiol, 96, 731–737.

138.

Saif

, Wang

, Vlasova

, Jung

, and Xiao

. (2019). Coronaviruses. In: Diseases of Swine. 488–523.

139.

Salimi

, and Hamlyn

. (2020). COVID-19 and crosstalk with the hallmarks of aging. J Gerontol Ser A, 75, e34–e41.

140.

Sang

, Tian

, Miller

, and Sang

. (2021). Epigenetic evolution of ACE2 and IL-6 genes: Non-canonical interferon-stimulated genes correlate to covid-19 susceptibility in vertebrates. Genes, 12, 154.

141.

Schäfer

, and Baric

. (2017). Epigenetic landscape during coronavirus infection. Pathogens, 6, 8.

142.

Seo

, Heo

, and Jang

. (2015). Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation. J Gen Virol, 96, 822–832.

143.

Seto

, and Yoshida

. (2014). Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb Perspect Biol, 6, a018713.

144.

Shereen

, Khan

, Kazmi

, Bashir

, and Siddique

. (2020). COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses. J Adv Res, 24, 91–98.

145.

Singh

, and Tscharke

. (2020). Herpes simplex virus latency is noisier the closer we look. J Virol, 94, e01701-19.

146.

Singh

. (2020). Can vitamins, as epigenetic modifiers, enhance immunity in COVID-19 patients with non-communicable disease?. Curr Nutr Rep, 9, 202–209.

147.

Smale

, Tarakhovsky

, and Natoli

. (2014). Chromatin contributions to the regulation of innate immunity. Annu Rev Immunol, 32, 489–511.

148.

Strahl

, and Allis

. (2000). The language of covalent histone modifications. Nature, 403, 41–45.

149.

Strollo

, and Pozzilli

. (2020). DPP4 inhibition: Preventing SARS-CoV-2 infection and/or progression of COVID-19?. Diabetes Metab Res Rev, 36, e3330.

150.

Suleyman

, Fadel

, Malette

, et al. (2020). Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in metropolitan Detroit. JAMA Netw Open, 3, e2012270.

151.

Taylor

, Latham

, and Woolhouse

. (2001). Risk factors for human disease emergence. Philos Trans R Soc Lond Ser B Biol Sci, 356, 983–989.

152.

The ENCODE Project Consortium. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature, 489, 57.

153.

Thomford

, Bope

, Agamah

, et al. (2019). Implementing artificial intelligence and digital health in resource-limited settings? Top 10 lessons we learned in congenital heart defects and cardiology. OMICS, 24, 264–277.

154.

Thomford

, Senthebane

, Rowe

, et al. (2018). Natural products for drug discovery in the 21st century: Innovations for novel drug discovery. Int J Mol Sci, 19, 1578.

155.

Thornbrough

, Jha

, Yount

, et al. (2016). Middle East respiratory syndrome coronavirus NS4b protein inhibits host RNase L activation. mBio, 7, e00258.

156.

Tollefson

. (2020). Climate vs coronavirus: Why massive stimulus plans could represent missed opportunities. Nature [Epub ahead of print]; DOI: 10.1038/d41586-020-00941-5.

157.

Tortorici

, and Veesler

. (2019). Structural insights into coronavirus entry. Adv Vir Res, 105, 93–116.

158.

Tregoning

, and Schwarze

. (2010). Respiratory viral infections in infants: Causes, clinical symptoms, virology, and immunology. Clin Microbiol Rev, 23, 74–98.

159.

Van Dam

, Huizing

, Mestach

, et al. (2020). SARS-CoV-2 and cancer: Are they really partners in crime?. Cancer Treat Rev, 89, 102068.

160.

Van Doremalen

, Bushmaker

, Morris

, et al. (2020). Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med, 382, 1564–1567.

161.

Vankadari

, and Wilce

. (2020). Emerging COVID-19 coronavirus: Glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect, 9, 601–604.

162.

Vavougios

. (2020). A data-driven hypothesis on the epigenetic dysregulation of host metabolism by SARS coronaviral infection: Potential implications for the SARS-CoV-2 modus operandi. Med Hypotheses, 140, 109759.

163.

Vijayvargiya

, Garrigos

, Almeida

NEC

, Gurram

, Stevens

, and Razonable

. (2020). Treatment considerations for COVID-19: A critical review of the evidence (or lack thereof). Mayo Clin Proc, 95, 1454–1466.

164.

Vokó

, and Pitter

. (2020). The effect of social distance measures on COVID-19 epidemics in Europe: An interrupted time series analysis. GeroScience, 42, 1075–1082.

165.

Vyas

, Kurian

, Bagchi

, et al. (2020). Vitamin D in prevention and treatment of COVID-19: Current perspective and future prospects. J Am Coll Nutr. 1–14.

166.

Walls

, Park

Y-J

, Tortorici

, Wall

, Mcguire

, and Veesler

. (2020). Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 181, 281–292.e6.

167.

Walls

, Tortorici

, Snijder

, et al. (2017). Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion. Proc Natl Acad Sci U S A, 114, 11157–11162.

168.

Wang

, Li

G-L

, Ming

S-L

, et al. (2020a). BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses. PLoS Pathog, 16, e1008429.

169.

Wang

, Zhang

, Wu

, et al. (2020b). Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell, 181, 894–904.e9.

170.

Weyand

, and Goronzy

. (2016). Aging of the immune system. Mechanisms and therapeutic targets. Ann Am Thorac Soc, 13,(Suppl 5), S422–S428.

171.

Whitworth

. (2020). COVID-19: A fast evolving pandemic. Trans R Soc Trop Med Hyg, 114, 241–248.

172.

Woolhouse

, and Gowtage-Sequeria

. (2005). Host range and emerging and reemerging pathogens. Emerg Infect Dis, 11, 1842.

173.

, and Zhang

. (2014). Reversing DNA methylation: Mechanisms, genomics, and biological functions. Cell, 156, 45–68.

174.

Xie

, and Zhu

. (2020). Association between ambient temperature and COVID-19 infection in 122 cities from China. Sci Total Environ, 724, 138201.

175.

Zhang

, and Kuchroo

, (2019). Epigenetic and transcriptional mechanisms for the regulation of IL-10. Semin Immunol, 44:101324.

176.

Zhao

, Fan

, and Frick

. (2010). Epigenetic alterations regulate estradiol-induced enhancement of memory consolidation. Proc Natl Acad Sci U S A, 107, 5605–5610.

177.

Zhou

, Chen

, Shannon

, et al. (2020a). Interferon-α2b treatment for COVID-19. Front Immunol, 11, 1061.

178.

Zhou

, Wang

, Tang

, Nussinov

, and Cheng

. (2020b). Artificial intelligence in COVID-19 drug repurposing. Lancet Digit Health, 2, e667–676.

179.

Zhu

, Zhang

, Wang

, et al. (2020). A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med, 382, 727–733.