The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in myalgic encephalomyelitis/chronic fatigue syndrome: A meta-analysis of public DNA methylation and gene expression data

Abstract

People with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report a high frequency of viral infections and flu-like symptoms during their disease course. Since this reporting is in line with different immunological abnormalities and altered gene expression profiles observed in the disease, we aimed to explore whether the expression of the human angiotensin-converting enzyme-2 (ACE2), the major cell entry receptor for SARS-CoV-2, is also altered in this neglected clinical population. In particular, a low expression of ACE2 is usually indicative of a high risk of developing COVID-19. We then performed a meta-analysis of public data on CpG DNA methylation and gene expression of this enzyme and its homologous ACE protein in peripheral blood mononuclear cells and related subsets. We found that patients with ME/CFS have decreased methylation levels of four CpG probes in the ACE locus (cg09920557, cg19802564, cg21094739, and cg10468385) and of another probe in the promoter region of the ACE2 gene (cg08559914). We also found a decreased expression of ACE2 but not of ACE in patients with ME/CFS when compared to healthy controls. Accordingly, in newly collected data, we found evidence for a higher proportion of samples with an ACE2 expression below the limit of detection in patients with ME/CFS than in healthy controls. Altogether, patients with ME/CFS could be at a higher COVID-19 risk when infected by SARS-CoV-2. To further support this conclusion, similar research should be conducted for other human cell entry receptors and other cell types, namely, those mainly targeted by the virus.

Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…We propose that similar alterations of the vascular system in response to a physical, infectious and / or emotional stressor (i.e., physiological insult) may also contribute to explain the emergence of ME/CFS. This is consistent with recent hypotheses describing vasoconstriction in muscle and brain as a principal element of ME/CFS (42)(43)(44)(45)(46), and findings of cerebral hypoperfusion (47)(48)(49) and intracranial hypertension (50) in ME/CFS patients. It is also consistent with studies that have shown that endothelial function is impaired in ME/CFS (51,52), both in large vessels and in the microcirculation (53, 54)-associated with redox imbalance (51).…”

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome

“…While patients with ME/CFS have enhanced local responses against SARS-CoV-2, systemic responses in plasma were similar to those of HDs. In a recent study, samples from patients with ME/CFS have demonstrated altered methylation and gene expression levels for the ACE and ACE2 locus, suggesting that the patients may have a higher risk of being infected with SARS-CoV-2 ( 36 ).…”

Lessons From Heat Stroke for Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Akin to heat stroke, several new hypotheses of ME/CFS suggest that vasoconstriction and hypoxia are central to its pathology—respectively focused on the consequence of ß2 adrenergic and M3 acetylcholine receptor autoantibodies ( 41 , 42 ), a potential reduction of ACE2 expression ( 43 ), and an abnormal immune response with a concomitant impact on endothelial function ( 44 ). In addition, postural orthostatic tachycardia syndrome (POTS) is a common comorbidity of ME/CFS ( 45 ), which is a complex disorder of the vascular system also associated with gastrointestinal dysfunctions ( 46 , 47 ).…”