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

halcyon

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It is not really possible to detect enterovirus infection in the brain without doing an autopsy, because enterovirus usually cannot be detected in the CSF, even in acute enterovirus brain infections.
It's indeed very rare to isolate enterovirus from CSF. Even in acute poliomyelitis it's rarely possible. That said, it has been done in ME (Innes 1970) and replicated (Levine 2001).
 

halcyon

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O'Neal and Hanson 2021 said:
...
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.
This is the crux of the issue and I'm happy to see someone finally point it out in a published article. None of the existing evidence for persistent infection in ME has been refuted to date. It's time to replicate using proven methods, and also utilize newer methods that have been developed to detect enteroviruses in chronic diseases, e.g. in Schubert, et al. 2019 and Genoni, et al. 2017. This should be done on a proper cohort that has been prescreened using microneutralizing serology so that only patients with serological titers indicative of active infection on at least two determinations are included.
 

halcyon

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This is the missing link in Dr. John Chia's interferon treatments for CFS. He used IFN alpha and beta. People got better, then at some point they relapsed because it never destroyed the virus entirely.
One of the problems with exogenously injected interferon is that it doesn't cross into the brain in any meaningful amounts. I've not looked if this is the case will all (sub)types of interferon, but it is the case with type I interferons like α and β. If ME is indeed caused by persistent CNS infection, this type of treatment is very unlikely to clear the infection, especially in only a few months. It's difficult even to knock out hepatitis C infection with many, many months of inteferon α combined with chain terminating antivirals, and in that case the interferon gets directly into the liver in large quantities. It's theoretically possible to do intrathecal interferon treatment, but my understanding is it's extremely dangerous and only done in severe situations such as SSPE.

Interferon does absolutely have an effect in ME though, two other studies also showed this, one of which also linked the effects with the presence of enterovirus infection.
 

halcyon

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But nobody really knows why non-cytolytic enterovirus persists in cells, seemingly impervious to the immune response.
Part of the blame likely lies in the immune system itself. Chronic immune activation downregulates the immune system in multiple ways. Mostly importantly, in my opinion, is through T cell exhaustion via activation of checkpoint systems such as PD-1. A potent enough chronic infection can cause effector T cells to become impotent or even kill themselves outright. One of the most striking things to me is when you look at the tissue sections that stain positive for enterovirus VP1 or dsRNA like that Chia produces, there are no immune cells to be found in the tissue. This could be due to the way the samples are processed or handled, but to me it also could indicate that the effector T cells that recognize VP1 or other enterovirus antigen have deleted themselves.
 

Pyrrhus

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One of the most striking things to me is when you look at the tissue sections that stain positive for enterovirus VP1 or dsRNA like that Chia produces, there are no immune cells to be found in the tissue.
One thing that struck me while reviewing the stained tissue sections that Chia produces is that the greatest staining is found at the region of the intestinal villi where the long-lived stem cells are found. If the long-lived stem cells are persistently infected with enterovirus, will that serve as a long-term reservoir of virus in the gut due to their long cellular life or will these cells lose their persistent infection since rapidly-dividing cells appear to be poor hosts for persistent enteroviral infections?
 

halcyon

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One thing that struck me while reviewing the stained tissue sections that Chia produces is that the greatest staining is found at the region of the intestinal villi where the long-lived stem cells are found. If the long-lived stem cells are persistently infected with enterovirus, will that serve as a long-term reservoir of virus in the gut due to their long cellular life or will these cells lose their persistent infection since rapidly-dividing cells appear to be poor hosts for persistent enteroviral infections?
There's a slide in one of his talks which shows the same tissue section stained first for dsRNA (J2 antibody) and then for VP1 (5D8/1 antibody) and the VP1 stained cells far outnumber the dsRNA stained cells. I don't recall knowing exactly what type of cells they were, but I found that interesting as well, though it could have just been an artifact of the sample being frozen in time, so to speak. Perhaps it just takes a small number of dsRNA persisted cells to seed infection constantly into the surrounding cells.
 

Boba

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@Pyrrhus
Unfortunately, there is no broad-spectrum antiviral that is effective and safe for treating RNA viruses.
Pfizer is working on an antiviral against Covid:
https://cen.acs.org/acs-news/acs-meeting-news/Pfizer-unveils-oral-SARS-CoV/99/i13

What do you think about it? Might this help to get rid of dsRNA? This Long Covid CFS thing is really frustrating. Obviously I‘m not considering that there may not be any dsRNA. However the news are stating that Covid might persist in the gut: https://www.bloomberg.com/news/arti...-may-have-prolonged-gut-infection-study-finds

I had GI symptoms before and during the infection. I‘m thinking maybe the solution for me is in the gut and That antivirals might help. This is a little bit naive reasoning I know…
 

sometexan84

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In the case of enteroviruses, it actually doesn't matter how strong or weak the blood-brain-barrier (BBB) is, as enteroviruses enter the brain via retrograde axonal transport, which bypasses the BBB completely.
Do you know if this has been shown w/ Coxsackie B?

Unfortunately, how common enteroviral brain infection is in ME/CFS is not known, because there have only been 3 post-mortem brain autopsies on enterovirus ME/CFS patients. But interestingly, all 3 brain autopsies were positive for enterovirus.
Weren't their symptoms very severe?

I would certainly be ok testing for encephalitis and meningitis, though I don't have memory loss, paralysis, etc.

Enterovirus muscle or gut infections in ME/CFS were also found in healthy controls. So we know from that that an enterovirus infection of the muscles and/or stomach does not necessarily lead to ME/CFS.
No one "knows" anything. Sounds right to me though.

Perhaps there are some other factors involved, such as for example the triggering of autoimmunity.
Yep, that sounds about right.

Or it may be that ME/CFS appears when there is an unusual immune response to this muscle or gut infection,
Yep, that sounds about right.
 

sometexan84

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One of the problems with exogenously injected interferon is that it doesn't cross into the brain in any meaningful amounts.
So, it looks like IFN lambda may actually help w/ the BBB and CNS infection.

administration of exogenous IFN-λ tightened the BBB, restricted viral neuroinvasion, reduced viral titers in the CNS, and protected mice from lethal viral infection
(2015) https://www.sciencedirect.com/science/article/pii/S107476131500268X

In this review, we highlight recent insights into IFN-λ functions, including its ability to restrict virus spread into the brain and to clear chronic viral infections in the gastrointestinal tract
 

Pyrrhus

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Thanks for sharing that.

It's definitely encouraging to see a new direct-acting antiviral (DAA) against coronavirus!

We can't get our hopes up too much, however, as most drugs in Phase I never make it to Phase III.

Do you know if this has been shown w/ Coxsackie B?
I'm not sure if retrograde axonal transport has been experimentally demonstrated with Coxsackie B.

It has, however, been demonstrated for Coxsackie A:
A nonpolio enterovirus with respiratory tropism causes poliomyelitis in intercellular adhesion molecule 1 transgenic mice (Dufresne and Gromeier, 2004)
https://www.pnas.org/content/101/37/13636

And for Enterovirus 71:
Retrograde Axonal Transport: a Major Transmission Route of Enterovirus 71 in Mice (Chen et al., 2020)
https://journals.asm.org/doi/full/10.1128/JVI.00236-07
 

Hip

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Weren't their symptoms very severe?
I imagine they must have been, as all three of these brain autopsies were performed on ME/CFS patients who committed suicide (and their relatives gave permission for the autopsies, in order to advance the science).

So maybe that is a factor which skews the results. We really need to get many more brain autopsies if we are going to see statistical significance. Unfortunately it is very rare to get donated bodies from ME/CFS patients.


Enterovirus CNS infection has not just been linked to ME/CFS, but also to the motor neuron disease ALS.

And recently, one new post-mortem study found evidence of enterovirus viral particles in the neurons of Parkinson's disease patients.
 
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I imagine they must have been, as all three of these brain autopsies were performed on ME/CFS patients who committed suicide (and their relatives gave permission for the autopsies, in order to advance the science).

So maybe that is a factor which skews the results. We really need to get many more brain autopsies if we are going to see statistical significance. Unfortunately it is very rare to get donated bodies from ME/CFS patients.


Enterovirus CNS infection has not just been linked to ME/CFS, but also to the motor neuron disease ALS.

And recently, one new post-mortem study found evidence of enterovirus viral particles in the neurons of Parkinson's disease patients.
Interesting. I won’t get too old (having a rare myopathy in it's clinical appearance and course very similar to ALS- maybe also due Coxsackie B4???? ). Hopefully it won't be necessary then because OMF will have already done it's work but I would donate my body for science...
 

sometexan84

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I emailed Dr. Jie Zhou, one of the authors of the below article, and I thought her response was quite interesting.

(2021) Human Intestinal Organoids Recapitulate Enteric Infections of Enterovirus and Coronavirus

Me: What are your thoughts on something like Pegylated Interferon Lambda for treatment of persistent Coxsackie and/or Echovirus infections in the GI tract?

Dr. Zhou: Thank you for your appreciation of our research. of course, enteroviruses are very sensitive to IFN lamda. it will definitely be an excellent drug for treating enterovirus infections.
 

sometexan84

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@Hip
One thing I'm curious about involves Dr. Chia's interferon treatments he used for enterovirus, where he treated them w/ interferon alpha, maybe in combo w/ something else, many patients have major improvement only to relapse months later.

But I noticed that he says the patients relapsed after a few month, and their viral titers returned back to pre-treatment level.

This is puzzling to me. I mean, you would think the titers would be at least a little bit less. But back to the exact same level as before treatment? It's as if the interferon fixed something that was causing symptoms, but didn't actually kill any of the virus at all????
 

Hip

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But I noticed that he says the patients relapsed after a few month, and their viral titers returned back to pre-treatment level.

This is puzzling to me. I mean, you would think the titers would be at least a little bit less. But back to the exact same level as before treatment? It's as if the interferon fixed something that was causing symptoms, but didn't actually kill any of the virus at all????
I would guess that the interferon treatment just knocks back the viral infection in the tissues, so that after interferon therapy, the patient is much better, and their antibody levels go down as a result of the viral infection being reduced (but not eliminated) by the treatment.

Then the infection grows back to its former size, the patient relapses, and antibody levels go back up.

Maybe the infection grows back to roughly the same size that it was before treatment, because there may be some sort of equilibrium point between the immune system and the infection, so the infection grows in size until it reaches that standoff equilibrium point. That's my guess.
 
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I would guess that the interferon treatment just knocks back the viral infection in the tissues, so that after interferon therapy, the patient is much better, and their antibody levels go down as a result of the viral infection being reduced (but not eliminated) by the treatment.

Then the infection grows back to its former size, the patient relapses, and antibody levels go back up.

Maybe the infection grows back to roughly the same size that it was before treatment, because there may be some sort of equilibrium point between the immune system and the infection, so the infection grows in size until it reaches that standoff equilibrium point. That's my guess.
But it's indeed interesting that they reach the exact same level. As if the former infected cells had a marker and the none infected cells don't