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The Enterovirus Theory of Disease Etiology in ME/CFS: A Critical Review (O'Neal and Hanson, 2021)

Pyrrhus

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The Enterovirus Theory of Disease Etiology in ME/CFS: A Critical Review (O'Neal and Hanson, 2021)
Adam J. O'Neal and Maureen R. Hanson
https://www.frontiersin.org/articles/10.3389/fmed.2021.688486/abstract

Abstract:
O'Neal and Hanson 2021 said:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle and heart.

To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fueled a decline in related studies over the past two decades.

This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen.

We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS. Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.
(spacing added for readability)

For more detailed excerpts, see this post:
https://forums.phoenixrising.me/thr...eal-and-hanson-2021.84191/page-6#post-2354207
 
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Pyrrhus

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Boba

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Ouh snap. Really hope COVID will make the business profitable for Pharma. One would need to target the dsRNA with a drug to get rid of it, if I get it right. At least crispr or Meganuclease type gene editing should help in 5 to 10 years. Hope I’m not talking rubbish here.
 

Pyrrhus

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More related discussions:

Enteroviruses Revisited
https://forums.phoenixrising.me/threads/enteroviruses-revisted.14478/

Evolutionary Genetics of Human Enterovirus 71: Origin, Population Dynamics, Natural Selection, and Seasonal Periodicity of the VP1 Gene (Tee et al., 2010)
https://forums.phoenixrising.me/thr...ed-by-another-coronavirus.86397/#post-2380702
https://forums.phoenixrising.me/thr...ed-by-another-coronavirus.86397/#post-2385878

CDC finally admits: Enterovirus D68 causes paralysis
https://forums.phoenixrising.me/threads/cdc-enterovirus-d68-causes-paralysis.75973/

The return of Polio to the USA? Is paralysis being mis-diagnosed as FND?
https://forums.phoenixrising.me/thr...nosed-a-surprising-statistical-anomaly.79074/

Parallels Between Post-Polio Fatigue and Chronic Fatigue Syndrome: A Common Pathophysiology?
https://forums.phoenixrising.me/thr...s-enterovirus-study.78166/page-2#post-2253921

Testing for Cellular mRNA translation? (global host mRNA translation shut-off by Enterovirus)
https://forums.phoenixrising.me/thr...na-translation-shut-off-by-enterovirus.81997/

Viral Extracellular Vesicles known as ‘Stealth Spheres’
https://forums.phoenixrising.me/threads/viral-extracellular-vesicles-known-as-stealth-spheres.75937/


Please note that the following articles are only viewable to Phoenix Rising members with at least 100 posts.

Disturbance of Hypothalamic Function and Evidence for Persistent Enteroviral Infection in Patients with CFS (Richardson, 1995)
https://forums.phoenixrising.me/thr...-of-hypothalamic-function-and-evidence.10086/

Viral Isolation from Brain in Myalgic Encephalomyelitis (Richardson, 2001)
Description of enterovirus detected in the brain during autopsy.
https://forums.phoenixrising.me/thr...rom-brain-in-myalgic-encephalomyelitis.10780/
 
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Pyrrhus

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Also possibly of interest:

I gave a small talk on Enterovirus A71 at UC Berkeley a number of years ago.

If anyone is interested, I am attaching the slides from my talk.
(For privacy reasons, I have removed my name from the slides.)
 

Attachments

  • EV71_SilentEpidemicPyrrhus.pdf
    615.6 KB · Views: 64

Murph

:)
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A curious thing:

I have a small child. Among children the disease hand foot and mouth disease is now endemic. It's a mild rash, mostly, with mild cold symptoms. There are several viruses that cause hand foot and mouth disease, including enteroviruses and coxsackie viruses.

Recently my kid caught hand foot and mouth disease. He was covered in spots but recovered quickly. I think I caught it too - I had a couple of spots in my mouth and a sniffle.

Here's the weird thing: For about a week after I recovered I felt amazing. I was full of energy and suddenly staying up late at night without any apparent consequence the next day. I began to wonder if my immune system was temporaril;y crunching a virus that had long been lingering in me. It didn't last long and I went back to normal (i.e. mild me/cfs).

Of course all this could be spurious correlation, but it makes me wonder.
 

Hip

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Here's the weird thing: For about a week after I recovered I felt amazing. I was full of energy and suddenly staying up late at night without any apparent consequence the next day. I began to wonder if my immune system was temporaril;y crunching a virus that had long been lingering in me. It didn't last long and I went back to normal (i.e. mild me/cfs).

That is quite remarkable.

It is in keeping with the fact that many long COVID ME/CFS patients report improvements after getting a SARS-CoV-2 vaccine (interestingly, greater improvements were observed with mRNA vaccines, like Pfizer or Moderna, compared to adenovirus vaccines like AstraZeneca).

That suggests when coxsackievirus B vaccines become available, regularly taking this vaccine might alleviate ME/CFS symptoms in patients whose illness is linked to CVB.

Researchers are working on coxsackievirus B vaccines, because they have been shown to prevent type 1 diabetes in mice, a disease linked to coxsackievirus B1 and B4.
 

nerd

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Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS.

A general problem in CFS/ME research. They rule out acute and productive viral infections and think that this excludes viral pathology. They test in the blood and implicitly assume that there can't be viral pathology elsewhere, in tissues or the CSF.
 

Pyrrhus

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There's a drug called Molnupiravir, which seems to work against Covid. Would this help with dsRNA? I'm not sure

Molnupiravir is still in the initial stages of research, it's safety has not yet been established.

Molnupiravir is a direct-acting antiviral drug (DAA) against RNA viruses, which simply means that the drug acts directly against a viral protein, not via some indirect antiviral effect.

Most direct-acting antiviral (DAA) drugs work either by targeting a viral protease protein or by targeting a viral polymerase protein. DAA that target a viral protease protein are generally called protease inhibitors. DAA that target a viral polymerase protein are either called a nucleoside analogue polymerase inhibitor or a non-nucleoside analogue polymerase inhibitor, depending upon how the drug interacts with the viral polymerase protein.

Nucleoside analogue polymerase inhibitors can be further divided into chain-terminating nucleoside analogues and mutagenic nucleoside analogues, depending upon how many drug molecules are needed to block a single strand of viral RNA from replicating itself. Whereas chain-terminating nucleoside analogues only need one or two drug molecules to block a single strand of viral RNA, mutagenic nucleoside analogues require many drug molecules to block a single strand of viral RNA.

As you might expect, the effective dosage for a mutagenic nucleoside analogue is much higher than the effective dosage for a chain-terminating nucleoside analogue. These much higher doses can turn minor side-effects into major safety considerations.

Unfortunately, molnupiravir is a mutagenic nucleoside analogue, so there is a large risk that it will not pass safety trials. But let's certainly hope for the best!
 

Boba

Senior Member
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I see. Higher dosage could result in major safety considerations, therefore passing the safety trials is critical. Let's assume it passes, is it guaranteed to target the viral dsRNA? There's still the question if this even is the problem of a long hauler like me.
 

Hip

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FYI Sci-Hub stopped adding new papers in December last year because of legal problems. :(

Oh no! I never heard about that. That's bad news!

The advent of Sci Hub some years back was so wonderful for the ME/CFS community that was interesting in ME/CFS research.

I remember so often you would find a very interesting paper, but only the abstract was available for free. It was always frustrating. Then Sci Hub came along, and all of sudden you were able to read all papers in depth.

A great deal of scientific research is funded by the taxpayer, so by rights the public should have access to it.
 

Pyrrhus

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I see. Higher dosage could result in major safety considerations, therefore passing the safety trials is critical. Let's assume it passes, is it guaranteed to target the viral dsRNA?

Excellent question.

Since direct-acting antiviral drugs (DAA) work by targeting viral proteins, what does that mean for viral single-stranded RNA (ssRNA) or for viral double-stranded RNA (dsRNA)?

First, here's a brief review of the virology of RNA viruses:
  • RNA viruses generally exist as single-stranded RNA (ssRNA) encased inside a protective shell.
  • When an RNA virus infects a cell, it proceeds through certain pre-defined stages in its "lifecycle".
  • The stages in the lifecycle include a replication stage, where the single strand of RNA (ssRNA) is used as a template to construct a complementary copy of the viral RNA on top of the original ssRNA. The result of this replication stage is a double-stranded RNA (dsRNA) that contains the original ssRNA bound to a complementary copy of the original ssRNA.
  • Then, the dsRNA separates into two strands: the original ssRNA and the complementary ssRNA.
  • The original ssRNA is usually then used to make viral proteins while the complementary ssRNA strand is then used as a template to make new copies of the original ssRNA. This is how an RNA virus makes viral proteins as well as new copies of itself.
Now, a human cell contains many enzymes that can degrade ssRNA, so the virus must act quickly to replicate itself before the cell degrades the viral ssRNA.

But a human cell has no enzyme that can degrade viral dsRNA, so if the virus gets "stuck" in the dsRNA stage of its lifecycle, the infected cell will have a hard time getting rid of the viral dsRNA.

There is evidence that some RNA viruses, such as flaviviruses and enteroviruses (and possibly coronaviruses), may exploit this loophole to persist inside cells by getting themselves "stuck" in the dsRNA stage of its lifecycle.

First, the bad news:
  • Direct-acting antiviral drugs (DAA) have no effect on the virus as long as it stays in the dsRNA stage of its lifecycle.
Now, the good news:
  • Double-stranded RNA (dsRNA), unlike double-stranded DNA, is an inherently unstable molecule, and there are a lot of things that can happen which will cause the dsRNA to separate into two strands of ssRNA.
  • Because of the inherent instability of dsRNA, the virus can not stay in this quasi-latent state forever. Unlike viruses that have a "true" latent state, the quasi-latent dsRNA state of RNA viruses may only last seconds, minutes, days, or possibly a few weeks.
  • According to one model of infected nerve cells, the dsRNA state will immediately separate into two ssRNA strands whenever the infected nerve cell activates. Thus, any neurological activity caused by physical or mental exertion will cause the dsRNA to separate, triggering renewed viral replication. If someone is taking a direct-acting antiviral drug (DAA) while physically or mentally exerting their self, then the drug has an opportunity to act on the virus, ideally preventing re-formation of the dsRNA state. This model remains theoretical pending experimental validation.