ACE2 encodes a key viral entry receptor for SARS-CoV-2 and is methylation sensitive
•
ACE2 is hypomethylated and overexpressed in lupus T cells suggesting an increased possibility of disseminated disease during SARS-CoV-2 infection
•
ACE2 demethylation might be exacerbated after SARS-CoV-2 infection due to increased oxidative stress
•
Demethylation in interferon-regulated and key cytokine genes might predispose lupus patients to cytokine storm in COVID-19
•
Maintaining remission in lupus is critical to prevent further demethylation and overexpression of ACE2
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.
