angiotensin II

The ACE2 enzyme breaks down angiotensin II (pictured).

The fact that the SARS-CoV-2 coronavirus enters cells through the same receptor that studies have implicated in the renin-angiotensin-aldosterone (RAA) paradox found in chronic fatigue syndrome (ME/CFS) has always been a bit eerie.

Two studies suggest that the activity of the ACE2 enzyme which transforms Ang II to Ang (1-7) and angiotensin to Ang (1-9) is reduced in ME/CFS. The inability to transform the pro-inflammatory and vasoconstricting Ang II to the anti-inflammatory Ang (1-7) is potentially a big deal in ME/CFS.

The Big Merge? Are Long COVID and ME/CFS Hypotheses Meshing?

In “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“, a diverse group of researchers (United Kingdom, Portugal, Germany, Austria/Chile, Spain, Poland, and Canada (!)) asked if ACE2 issues found thus far might leave people with ME/CFS at a greater risk from the coronavirus. The senior author of the study was Nuno Sepulveda – a relative newcomer to ME/CFS, who has jumped in with both feet.

A Never-Ending Immune Battle in ME/CFS? The Regulatory T-cell/Herpesvirus Hypothesis

The group did meta-analyses of publicly available data on DNA methylation and gene expression of ACE2 and ACE from six small ME/CFS studies, in patients with systemic lupus erythematosus, as well as mRNA (gene expression) data of these two genes from a cohort of women with ME/CFS and healthy controls.

The authors attempted to determine if epigenetic shifts had altered the expression of the ACE and ACE2 enzymes in ME/CFS. Epigenetic shifts occur when an event alters the expression of our genes. These events – the onset of ME/CFS could clearly be one – occur throughout our lifespan. Over time they alter the expression of our genes markedly – essentially obscuring the genetic template we were born with. The idea that an epigenetic shift occurred which caused or contributed to ME/CFS has resulted in quite a few studies being done.

The question was: had something shifted ACE2 expression in ME/CFS, and if so, did that mean people with ME/CFS were at greater risk of a coronavirus infection?

The coronavirus appears to downregulate the activity of the ACE2 enzyme. That’s downregulation poses a particular problem for people with cardiovascular diseases, diabetes, and other conditions, who already have low ACE2 levels. The coronavirus infection exacerbates the already low ACE2 expression causing the blood vessels to narrow (vasoconstriction), increased oxidative stress, and inflammation. Reduced ACE2 expression in people with ME/CFS could conceivably put them at a higher risk for severe coronavirus response.

This question isn’t important simply for the implications it might have on how people with ME/CFS fare after getting the coronavirus. The reduced expression of the ACE2 gene, if it was found, might also be able to help explain why the renin-angiotensin-aldosterone system could be reducing blood flows, impairing blood volume, inhibiting mitochondrial functioning, and others in ME/CFS.

Hypothesis Predicts Major Failure Point in Chronic Fatigue Syndrome (ME/CFS)

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The authors reported that they could not determine if the people with ME/CFS were at more risk from the coronavirus. While they did have access to numerous small studies, some old bugaboos surfaced: some data was not available, some studies used cells that did not express ACE2 genes well, some studies had unclear data, and some studies used case definitions that are not recommended for research.

DNA methylation

DNA methylation changes who we are as genetic beings. A methylation event could have sparked ME/CFS.

While they couldn’t come to clear-cut conclusions, some things did stand out. Four probes found decreased methylation of the ACE gene and one found decreased methylation of the ACE2. The low methylation rates finding suggested that the ACE gene, in particular, was more highly expressed or active in ME/CFS.

Their metanalysis, however, suggested the opposite. The expression of the ACE2 gene appeared to be significantly reduced in ME/CFS. That finding was partially confirmed by new data which found that ME/CFS patients tended to have more samples than healthy controls which picked up no evidence of ACE2 expression.

The Gist

  • The coronavirus uses a receptor called ACE2 to enter cells. In a rather bizarre coincidence, the ACE2 enzyme has also been implicated in ME/CFS.
  • Given that, the researchers questioned whether people with ME/CFS are at greater risk from a coronavirus infection and should be given priority with vaccines.
  • People with other diseases which feature impaired ACE2 functioning, such as diabetes and cardiovascular diseases, appear to be at more risk from a coronavirus infection.
  • These researchers surveyed past studies to determine if epigenetic modifications to ACE/ACE2 to see if these genes had been turned off – thus inhibiting the expression of the ACE2 enzyme.
  • The study was hampered by a variety of methodological problems, but it did uncover some evidence suggesting that the activity of the ACE2 gene may have been epigenetically turned down in ME/CFS.
  • Two surveys also suggest that people with ME/CFS may indeed be having a much more difficult time with the virus than usual.
  • The authors also proposed that the virus may be able to enter other cells in the body through different receptors – including one receptor which has been studied in ME/CFS.
  • In the end, the authors could not say that people with ME/CFS were at more risk from a coronavirus infection but urged that studies assess epigenetic modifications to the ACE2 receptor ME/CFS.
  • We should get more data on how people with ME/CFS fare during a coronavirus infection from the YOU+ME Patient Registry.
  • On a separate note, Nancy Klimas is following how people with ME/CFS do after a coronavirus vaccination.

That suggested people with ME/CFS might have a harder time with a coronavirus infection. Plus, two more data points may apply. A joint ME Action/Action for ME survey found that more than 2/3rds of ME patients who had COVID-19 reported their symptoms were still worse six months later. Similarly, a Health Rising survey more than 40% of people with ME/CFS/FM reported they still had not returned to baseline three months after getting COVID-19 on. Solve ME’s Patient Registry is also, I believe, collecting data on how people with ME/CFS fare during a coronavirus infection.

The analyses were done on a broad class of immune cells called PBMCs (peripheral blood mononuclear cells) which do not express the ACE2 gene particularly well. Given that, it’s not clear that the ME/CFS findings from the PBMCs would translate to the main targets of the coronavirus – the epithelial and endothelial cells in the lungs. The authors urged that the epigenetic modifications to the ACE2 genes in these cells be assessed in ME/CFS.

Other Tricks Up the Coronavirus’s Sleeve?

There are other possibilities. It’s not clear that the epithelial and endothelial cells in the lungs are the only cells the coronavirus infects. Some evidence suggests that the virus may be able to use different receptors to enter other cells. If those cells are more vulnerable to infection in ME/CFS that could spell trouble.

The virus appears to use the TMPRSS2 receptor to trigger the same protease to degrade ACE2. Much the same thing may be happening with a stress-response protein called ADAM17.SInce ACE2 appears to be a potentially vulnerable point for ME/CFS with regard to a coronavirus infection people with ME/CFS could be at risk if either of the above is happening.

A third protein (Dipeptidyl peptidase-4 (DPP4)) that’s been able in the past, to facilitate the entry of past coronaviruses such as MERS into the cell, provides an intriguing option for ME/CFS. This DPP4 protein is well expressed on PBMCs, and studies suggest that it may be able to interact with the SARS-CoV-2 virus responsible for the pandemic. In fact, DPP4 blockers have been found to be helpful in severe patients with COVID-19.

Two studies suggesting that DPP4 receptors are increased in the NK and T-cells in ME/CFS. If that’s so ME/CFS patient’s NK and T cells could provide the coronavirus more opportunities to invade. Nancy Klimas was interested enough in these receptors to investigate the possibility that they could provide a biomarker for ME/CFS in two studies.

One study found that an increased percentage of NK cells carried the DPP4 receptor. Her next more in-depth study concluded that both the density of the DPP4 receptors on the NK cell surfaces and the concentration of the DPP4 enzyme in the serum were reduced in ME/CFS. So, while more cells expressed the receptor, they tended to contain less of it – a confusing situation that might be explained by the immune exhaustion some think is happening in ME/CFS.

While it’s not clear what it does appear that something is up with the DPP4 receptor in ME/CFS patients PBMC’s. The authors of the current paper proposed that, if it becomes clear that the SARS coronavirus is able to enter PBMCs through the DPP4 receptor, then research into this receptor in ME/CFS “should be prioritized“.


coronavirus infection ME/CFS

While some evidence suggests people with ME/CFS could be at greater risk from a coronavirus infection, the authors could not definitively say so. More research is needed.

In the end, the authors could not say that people with ME/CFS were or were not at risk of a more severe response to the coronavirus, and therefore should be given priority with regards to vaccinations (or boosters).

They did, however, find some data suggesting that people with ME/CFS might be more at risk from the virus. The fact that people with diseases with ACE2 inhibition are at greater risk from a coronavirus infection suggests that ACE2 impairment may put people with ME/CFS at risk. Some survey data suggests people with MECFS might be more at risk as well. It should also be noted that adrenal insufficiency by itself could conceivably be causing the low ACE2 functioning in ME/CFS.

The authors concluded, that more research is needed – particularly in epithelial/endothelial cells – but also in other cells the virus may be able to invade. Clearly, more research is also needed into ACE2 functioning in ME/CFS and postural orthostatic tachycardia syndrome (POTS) as the same scenario may apply to POTS.

Nancy Klimas, by the way, has begun a study assessing both symptomatic and immune responses to the mRNA vaccines in ME/CFS patients that should help us understand why some people are better with the vaccines and why some people are doing worse. (Solve ME’s Patient Registry is also collecting data on the effects of the coronavirus vaccine).

Dr. Klimas is also in the midst of a long-COVID study that will follow 1,000 people with documented coronavirus infections for 4 years. A subset of them will be intensely analyzed over time.

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