Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients

Abstract

Infection caused by SARS-CoV-2 can result in severe respiratory complications and death. Patients with a compromised immune system are expected to be more susceptible to a severe disease course. In this report we suggest that patients with systemic lupus erythematous might be especially prone to severe COVID-19 independent of their immunosuppressed state from lupus treatment. Specifically, we provide evidence in lupus to suggest hypomethylation and overexpression of ACE2, which is located on the X chromosome and encodes a functional receptor for the SARS-CoV-2 spike glycoprotein. Oxidative stress induced by viral infections exacerbates the DNA methylation defect in lupus, possibly resulting in further ACE2 hypomethylation and enhanced viremia. In addition, demethylation of interferon-regulated genes, NFκB, and key cytokine genes in lupus patients might exacerbate the immune response to SARS-CoV-2 and increase the likelihood of cytokine storm. These arguments suggest that inherent epigenetic dysregulation in lupus might facilitate viral entry, viremia, and an excessive immune response to SARS-CoV-2. Further, maintaining disease remission in lupus patients is critical to prevent a vicious cycle of demethylation and increased oxidative stress, which will exacerbate susceptibility to SARS-CoV-2 infection during the current pandemic. Epigenetic control of the ACE2 gene might be a target for prevention and therapy in COVID-19.

Keywords: ACE2; COVID-19; Epigenetics; Interferon; Lupus; Methylation; SARS-CoV-2.

Fig. 1

A) DNA hypomethylation of ACE2 in a subset of CD4⁺ T cells characterized by expression of KIR genes and high levels of CD11a (KIR⁺CD11a^hi) compared to autologous KIR⁻CD11a^low CD4⁺ T cells in lupus patients. The KIR⁺CD11a^hi T cell subset has been previously shown to overexpress other methylation sensitive genes in lupus patients including CD40LG, also located on the X chromosome. (*, P < .01, corrected for multiple testing and derived using GenomeStudio (Illumina)). B) Normalized mRNA expression values of ACE2 in CD4⁺ T cells isolated from lupus patients compared to healthy controls. These data were extracted from Gene Expression Omnibus (GEO accession: GSE4588) (P = .01; Mann-Whitney test). C) Demethylation of a CpG site in the 3′-untranslated region of ACE2 (cg23232263) in CD4⁺ T cells from lupus patients with a history of kidney involvement compared to age, sex, and ethnicity matched healthy controls. DNA methylation beta values were extracted from genome-wide methylation data generated using the HumanMethylation450 array (P = .03; Mann-Whitney test) D) Normalized mRNA expression values of ACE2 in the same CD4+ T cell samples from lupus patients and controls shown in panel C. Values were extracted from Affymetrix U133 plus 2.0 array data (P = .18; Mann-Whitney test).

Fig. 2

Schematic presentation suggesting mechanisms that might increase susceptibility to and severity of COVID-19 in lupus patients. Lupus is characterized by a DNA methylation defect which has been demonstrated in multiple cell types. SARS-CoV-2 utilizes ACE2 as a receptor for entry into cells. ACE2 is a methylation-sensitive gene located on the X chromosome. Lupus patients show evidence of ACE2 hypomethylation possibly mediating ACE2 overexpression which will increase the likelihood of SARS-CoV-2 infection. Viral infections are associated with increased oxidative stress, which is known to induce lupus flares and induce further DNA demethylation. Hypomethylation and overexpression of ACE2 in T cells (and possibly other cell types) will facilitate T cell viral infection and viral dissemination resulting in a more severe COVID-19. Interferon-regulated genes and other inflammatory cytokine genes are hypomethylated in lupus patients and thereby epigenetically primed for transcription upon interferon exposure resulting from viral immune response. This epigenetic priming might increase the possibility of cytokine storm in lupus patients.