The epigenetic implication in coronavirus infection and therapy

Abstract

Epigenetics is a relatively new field of science that studies the genetic and non-genetic aspects related to heritable phenotypic changes, frequently caused by environmental and metabolic factors. In the host, the epigenetic machinery can regulate gene expression through a series of reversible epigenetic modifications, such as histone methylation and acetylation, DNA/RNA methylation, chromatin remodeling, and non-coding RNAs. The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, and spread worldwide, causes it. COVID-19 severity and consequences largely depend on patient age and health status. In this review, we will summarize and comparatively analyze how viruses regulate the host epigenome. Mainly, we will be focusing on highly pathogenic respiratory RNA virus infections such as coronaviruses. In this context, epigenetic alterations might play an essential role in the onset of coronavirus disease complications. Although many therapeutic approaches are under study, more research is urgently needed to identify effective vaccine or safer chemotherapeutic drugs, including epigenetic drugs, to cope with this viral outbreak and to develop pre- and post-exposure prophylaxis against COVID-19.

The Role of Immunogenetics in COVID-19

“…A huge comprehension of the impact of genetic/epigenetic variants on immune mechanisms would offer the chance to: (i) identify those molecular pathways that are impaired in the setting of the immune response against SARS-CoV-2, leading to a more severe disease and to a more difficult resolution of the infection; (ii) concentrate the efforts on the design of a personalized approach for those patients presenting variants associated with a notable risk of altered lymphocyte distribution, uncontrolled or suboptimal immune response and cytokine storm syndrome; (iii) detect molecular defects common to other diseases that may be considered as possible targets in terms of drug repurposing [ 10 , 12 , 89 , 233 , 234 , 235 , 236 , 237 ]. This specific pandemic situation requires a global coordinated approach to face the disease in a short time with the most limited loss of human lives.…”

“…It is pretty evident that a number of factors contribute to determine SARS-CoV-2 infection susceptibility and COVID-19 severity ( Figure 1 ), and that such a high number of new infections/hospitalized cases put extreme pressure on the global web of health care systems, creating the premises for the urgent need for a shared scheme to face the pandemic [ 2 , 214 , 216 ]. Together with public health measures to control the spread of the infection, stratifying patients according to the risk of developing a life-threatening disease could be a winning strategy to ensure the highest reachable survival rates while waiting for the completion of a global vaccination plan or the introduction of SARS-CoV-2 specific antiviral drugs [ 2 , 89 , 215 ]. The elaboration of an algorithm to calculate the probability of requiring hospitalization and to predict the efficacy and safety of early treatment/targeted treatment is an attractive perspective.…”

“…This strong resemblance to immunosenescence makes COVID-19 a possible scenario to deepen the knowledge about the molecular basis affecting normal immune cell metabolism/lifespan/turnover and to determine the importance of genetic variants and epigenetic modifications behind the appearance of inflammaging and immunosenescence [ 66 , 85 , 86 , 87 , 88 ]. Furthermore, the improvement of our understanding of the relationship between immunogenetics and immunosenescence (including inflammaging) would be crucial in the design of a therapeutic strategy specifically for older COVID-19 patients [ 66 , 68 , 69 , 89 ].…”

“…Similarly, PHA stimulated T cells from a patient with AR IFNAR1 deficiency had impaired IFNAR1 expression and response to type I IFNs. Then, the authors checked the functional consequences of IRF7 and IFNAR1 defects on SARS-CoV-2 susceptibility in vitro, taking into account that angiotensin-converting enzyme 2 (ACE2) works as a receptor for SARS-CoV-2, and that transmembrane protease serine protease 2 (TMPRSS2) processes SARS-CoV-2 S protein and activates viral entry [ 2 , 89 ]. Thus, they noticed that TLR3−/−, TLR3+/−, IRF7−/−, and IFNAR1−/− fibroblasts previously transduced with ACE2 and TMPRSS2 were more susceptible to SARS-CoV-2 infection in vitro vs. cells from control subjects but were rescued by transduction of wild type IRF7 or IFNAR1 .…”

Epigenetic mechanisms influencing COVID-19

“…Another proinflammatory cytokine upregulated upon SARS-CoV-2 infection is GM-CSF, which is currently a therapeutic target in clinical trials against COVID-19 (Lang, Lee, Teijaro, Becher, & Hamilton, 2020) (NCT04400929, NCT04341116). Novel therapies against elevated cytokines and overall therapeutic implications for COVID-19 are discussed in detail elsewhere (Atlante et al, 2020;Bradshaw, Seeds, Miller, Mahajan, & Curtis, 2020;Crimi, Benincasa, Figueroa-Marrero, Galdiero, & Napoli, 2020). In summary, the type of immune response described above is referred to as a "cytokine storm" which causes excessive influx of immune cells at the site of infections.…”