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

Authors: Sawalha, AH et al. Link to paper: https://www.medrxiv.org/content/10.1101/2020.03.30.20047852v1.full.pdf

Journal/ Pre-Print: medRxiv

Key Words: Epigenetics, autoimmunity, lupus, ACE2, methylation

Research Highlights

1. Reduced methylation level and increased mRNA levels of ACE2 in lupus patients

2. ACE2 gene hypomethylation in lupus patients might lead to increased susceptibility to and heightened severity of COVID-19, especially during lupus flares.

Summary 

In this study, the authors consider that patients with the autoimmune disease lupus might be especially prone to severe COVID19 due to hypomethylation of ACE2. Lupus patients often have expansion of a demethylated T cell subset, which contributes to T cell autoreactivity. Sawalha et al. show that there is significant hypomethylation of ACE2 at multiple CpG sites in this T cell subset, and that there is a significantly higher expression of ACE2 mRNA in CD4+ T cells from lupus patients versus healthy controls. They conclude that preventing lupus flares in patients is therefore of critical importance during this pandemic.

Impact for SARS-CoV2/COVID19 research efforts

Others: Epigenetic dysregulation of ACE2

Study Type

· In silico study / bioinformatics study

· In vitro study

Strengths and limitations of the paper

Novelty: The concept of epigenetic dysregulation of ACE2 gene

It is the first paper to discuss the effects of SARS-CoV2 in lupus patients

Standing in the field: There is literature supporting methylation of ACE2 under disease conditions, but the relation between it and COVID is mainly based on speculation in this paper.

Appropriate statistics: On the whole correct although more information on sample size should be provided

Viral model used: N/A

Translatability: Difficult

Main limitations: Only ACE2 mRNA levels are measured, not protein – do increased mRNA levels correspond to increased functional receptor on the cell surface?

They do not infect cells with SARS-CoV2, therefore it is not clear that the higher expression of ACE2 mRNA in the CD4+ T cells of lupus patients results in higher infection rates in these cells

It is not shown/known that KIR+ CD11ahi CD4+ CD28+ T cells are infected by SARS-CoV2 during infection in vivo

This study is exclusively in T cells from the blood, so the relevance of this to lung tissue is not established

Does infection with SARS-CoV2 cause oxidative stress?

Overall, very few data with too many speculations