COVID-19 Is a Multi-Organ Aggressor: Epigenetic and Clinical Marks

Abstract

The progression of coronavirus disease 2019 (COVID-19), resulting from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be influenced by both genetic and environmental factors. Several viruses hijack the host genome machinery for their own advantage and survival, and similar phenomena might occur upon SARS-CoV-2 infection. Severe cases of COVID-19 may be driven by metabolic and epigenetic driven mechanisms, including DNA methylation and histone/chromatin alterations. These epigenetic phenomena may respond to enhanced viral replication and mediate persistent long-term infection and clinical phenotypes associated with severe COVID-19 cases and fatalities. Understanding the epigenetic events involved, and their clinical significance, may provide novel insights valuable for the therapeutic control and management of the COVID-19 pandemic. This review highlights different epigenetic marks potentially associated with COVID-19 development, clinical manifestation, and progression.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; cytokine storm; epigenetics; multi-organ; pro-inflammatory cytokines.

Figure 1

Chromatin structure. (A) A 147bp DNA wraps around the histone octamer with two copies of each of the histones H2A, H2B, H3, and H4. Various epigenetic mechanisms that modify chromatin, such as DNA methylation and histone modifications, are highlighted. DNA and histone methylation collaborate with different modifying enzymes and creates a tightly packed chromatin and suppress gene transcription by preventing the transcription machinery from binding DNA. Histone acetylation perturbs structural electrostatic interactions between the DNA and histones, resulting in the less compact structure of chromatin structure. This allows DNA access by transcription factors that promote gene transcription. (B) Writing, erasing, and reading chromatin methylation markers are highlighted. These mark various sites on the tail and globular domains of histones. Writers and erasers are methyltransferases and demethylases, respectively. These are recognised by distinct effector proteins called readers. (Created with BioRender.com) ac, Acetylation; DNMT, DNA methyltransferase; GLP, G9a-like protein; GNATs, Gcn5-related N-acetyltransferases; HATs, Histone acetyltransferases; HDACs, Histone deacetylases; JmjC, Jumonji C; KDM, Histone lysine demethylases; LSD, Lysine-specific demethylases; MBDs, Methyl-CpG binding domains; me, Methylation; MLL, Mixed-lineage leukaemia; PHD - Plant homeodomain; PRC2, Polycomb repressive complex 2; p300/CBP, p300 and cyclic AMP response element-binding protein; SET1, Suppressor of variegation 3–9, Enhancer of Zeste, Trithorax 1; SIRT, sirtuins; TET, Ten-eleven translocation; UTX1, Ubiquitously transcribed tetratricopeptide repeat, X chromosome 1.

Figure 2

Potential underlying mechanisms of SARS-CoV2 invasion and multi-organ induced damage. Inflammation mediated by SARS-CoV-2 infection and its primary receptor ACE2 drive multi-organ failure in severe COVID-19 cases. ACE2 is widely expressed in multiple organs, and its suppression may aggravate COVID-19 severity and negatively impacts multiple organs via regulation of RAS. Moreover, this leads to severe cases of COVID-19 that are often associated with ARDS and increased mortality rate, partially mediated by the overproduction of pro-inflammatory cytokines (cytokine storm). Cytokine storm results from increased levels of inflammatory mediators, endothelial dysfunction, coagulation abnormalities, and infiltration of inflammatory cells into the organs. This may be characterised by elevated levels of interleukin-6 (IL-6), nuclear factor kappa B (NFκB), and tumour necrosis factor-alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes. The involvement of different organs in severe patients is characterised by multi-organ failure and a broad spectrum of haematological abnormalities and neurological disorders that lengthen the hospitalisation duration and increase mortality. The most important mechanisms are related to the direct and indirect pathogenic features of SARS-CoV2 infection. (Created with BioRender.com). ACE2, Angiotensin I-converting enzyme-2; AoDO2, First alveolar-arterial oxygen gradient; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; IFN-γ, Interferon-gamma; IL-1β, Interleukin- 1β; IL-4/6/10, Interleukin- 4/6/10; TNF-α, Tumour necrosis factor-alpha; MCP-1, Monocyte chemoattractant protein-1.

Figure 3

Overview of sex-based differences in the immune response to COVID-19. The diagram shows how X-chromosome inactivation escapee genes may underlie sex bias differences in COVID-infection, severity, and mortality. Sex-bias differences in COVID-19 may be linked to ACE2, the primary receptor that enables SARS-CoV-2 infection. Having double X-chromosomes protects women against increased susceptibility to COVID-19 infection and associated severe complications as compared to men who have just a single X-chromosome. ACE2 is an X-chromosome-linked gene that escapes X-inactivation, a phenomenon that suppresses gene transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. This means that women have twice more genetic instructions to transcribe ACE2 and many more X-chromosome-linked immunoregulatory genes that protect women from increased COVID-19 susceptibility and associated severe complications. (Created with BioRender.com). ACE2, Angiotensin I-converting enzyme-2; COVID -19, Coronavirus disease 2019; SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2; XCI, X-chromosome inactivation; XIST, X-inactive specific transcript.

Figure 4

Potential COVID-19 related epigenetic alterations and clinical implications. Like many other viruses, SARS-CoV-2 may trigger various epigenetic alterations such as global DNA methylation and histone modifications, which synergistically cooperate in influencing and driving the course of COVID-19 and sex-bias differences. In response to increased viral replication, the infected host cells may set off an epigenetic signature to antagonise the virus as part of innate immune defence machinery. Part of this epigenetic landscape may be subverted to benefit the virus and its propagation, leading to enhanced and systemic COVID-19 infection that promotes severe complications. (Created with BioRender.com). cGAS, Cyclic GMP–AMP synthase; CIITA, The major histocompatibility class (MHC) II transactivator; DNMTs, DNA methyltransferases; ECE1, endothelin Converting Enzyme 1; FOXP3, Forkhead box protein P3; GCN5, General control non-repressed 5 protein; HATs, Histone acetyltransferase; HDAC, Histone deacetylase; HIF-1α, Hypoxia-inducible factor-1α; HSPA1L, Heat shock protein family A (Hsp70) member 1-like; IFN-γ, Interferon gamma; IFN-β, Interferon-β; IL-6, Interleukin- 6; IRF2, Interferon regulatory factor 2; IRF3, Interferon regulatory factor 3; ISG15, Interferon-stimulated gene 15; JmjC, Jumonji C; KDM, Histone lysine demethylases; LSD, Lysine-specific demethylases; MBDs, Methyl-CpG binding domains; MyD88, Myeloid differentiation factor 88; MLL, Mixed-lineage leukaemia; NF-κB, Nuclear factor kappa B; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; PDIA3, Protein disulfide isomerase family A member 3; PEG10, Paternally expressed gene 10; PHD, Plant homeodomain; PRC, Polycomb repressive complex; p300/CBP, p300 and cyclic AMP response element-binding protein; STAT-3, Signal transducer and activator of transcription-3; STAT-6, Signal transducer and activator of transcription-6; SET1, Suppressor of variegation 3–9, enhancer of zeste, trithorax 1; SIRT, Sirtuins; STING, Stimulator of interferon genes; TAP2, Transporter 2, ATP Binding Cassette Subfamily B Member; TBK1, Tank binding kinase 1; TET, Ten-eleven translocation; TLR, Toll-like receptors; TNF-α, Tumour necrosis factor-alpha; UTX1, Ubiquitously transcribed tetratricopeptide repeat, X chromosome 1; VEGF-D, Vascular endothelial growth factor D.