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

Clin Immunol. 2020 Jun;215:108410. doi: 10.1016/j.clim.2020.108410. Epub 2020 Apr 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Betacoronavirus / immunology
  • Betacoronavirus / pathogenicity
  • CD11a Antigen / genetics
  • CD11a Antigen / immunology
  • COVID-19
  • Coronavirus Infections / complications
  • Coronavirus Infections / epidemiology
  • Coronavirus Infections / genetics*
  • Coronavirus Infections / immunology
  • Cytokines / genetics
  • Cytokines / immunology
  • DNA Methylation
  • Disease Progression
  • Epigenesis, Genetic*
  • Genetic Predisposition to Disease*
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology
  • Humans
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / immunology
  • Lupus Erythematosus, Systemic / complications
  • Lupus Erythematosus, Systemic / epidemiology
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / immunology
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Oxidative Stress / genetics
  • Oxidative Stress / immunology
  • Pandemics*
  • Peptidyl-Dipeptidase A / genetics*
  • Peptidyl-Dipeptidase A / immunology
  • Pneumonia, Viral / complications
  • Pneumonia, Viral / epidemiology
  • Pneumonia, Viral / genetics*
  • Pneumonia, Viral / immunology
  • Protein Binding
  • Receptors, KIR / genetics
  • Receptors, KIR / immunology
  • SARS-CoV-2
  • Signal Transduction
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / immunology
  • Viremia / complications
  • Viremia / epidemiology
  • Viremia / genetics*
  • Viremia / immunology


  • CD11a Antigen
  • Cytokines
  • Interferon Regulatory Factors
  • NF-kappa B
  • Receptors, KIR
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2