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

[Boba]

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.

@Pyrrhus
I‘m thinking about PEM when I read this. Would the ssRNA cause an immune reaction?

 

[Pyrrhus]

@Pyrrhus
I‘m thinking about PEM when I read this. Would the ssRNA cause an immune reaction?

Not immediately, but the presence of ssRNA would stimulate viral replication, which eventually (perhaps the following day) might stimulate an immune or neuroinflammatory response.

 

[sometexan84]

It is absolutely, entirely possible.

But there has been no funding for research into such antiviral treatments, nor has there been any serious interest in RNA viruses from pharmaceutical companies for the last 40 years, with the notable exceptions of the Hepatitis C virus, and the influenza virus.

Hep C, and Influenza... both of which have either studies or trials demonstrating the effectiveness of Interferon Lambda treatment (Peginterferon-Lambda), a Type III interferon.

Also, an antiviral treatment for coronavirus being studied, trialed, and already shown success..... Peginterferon Lambda.

Interferon Lambda also shown as strong antiviral for Rotavirus, Norovirus, and Rhinovirus. And all these are RNA viruses with an affinity for epithelial cells and epithelial barriers as their reservoir.

And of course, it's the exact same w/ Enterovirus (Coxsackie and Echo).

 

[Pyrrhus]

Hep C, and Influenza... both of which have either studies or trials demonstrating the effectiveness of Interferon Lambda treatment (Peginterferon-Lambda), a Type III interferon.

Thanks for bringing that up.

I'm not as informed about IFN-lambda/IL-28 as I would like to be, but trials with type I interferons generally showed promise only when combined with a direct-acting antiviral drug (DAA). These trials also demonstrated that including type I interferons in such a combination led to intolerable side effects, including brain inflammation. (The same might also be true for high doses of drugs that stimulate the intracellular interferon pathway, such as Ampligen or nitazoxanide.)

The ideal treatment would only consist of one or more DAAs that directly target the virus, without any inflammatory side effects.

Hope this helps.

 

[sometexan84]

Thanks for bringing that up.

I'm not as informed about IFN-lambda/IL-28 as I would like to be, but trials with type I interferons generally showed promise only when combined with a direct-acting antiviral drug (DAA). These trials also demonstrated that including type I interferons in such a combination led to intolerable side effects, including brain inflammation. (The same might also be true for high doses of drugs that stimulate the intracellular interferon pathway, such as Ampligen or nitazoxanide.)

The ideal treatment would only consist of one or more DAAs that directly target the virus, without any inflammatory side effects.

Hope this helps.

Right, one reason the side effects were severe is because Type I interferon affects the whole body. But Type III (lambda) works at just the organ barriers (epitheliums), like intestine, lung, etc.

IFN Type III (Lambda) was only recently discovered.

I believe it's the absolute best shot at removing persistent Enterovirus infection.

This Type III interferon is a very potent antiviral against enterovirus, and the natural IFN III is pretty much how the body gets rid of the acute EV infection in the first place.

Problem is, those of us w/ persistent EV had (at some point) a weak enough intracellular immune response to allow EV to take hold, where it then cleaves the proteins in the infected cells in order to block the IFN III response. That's how it evades, it blocks IFN III because IFN III will destroy it.

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.

IFN Lambda however has possibly the best antiviral effect on enterovirus, it works exactly where the virus is, and there are way less side effects so you can use it for longer.

 

[sometexan84]

If you want to learn more...

Chronic Enterovirus B is usually in your gut (GI tract)*

• Enteroviruses invade gut/intestinal mucosa, as this is a reservoir for viral persistence. The mucosa consists of epithelial cells
• Enterovirus found in parietal cells of ME/CFS patients. (Parietal cells are epithelial cells)
• Again, Enterovirus targets the gastrointestinal epithelium
• GI Tract, or intestinal epithelium, or intestinal mucosa, all same thing

* even if you know you have chronic enterovirus b in places other than gut (e.g. brain, pancreas, heart), it still likely means you have the infection in your GI tract still as well.

(GI tract) Intestinal epithelial cells are infected

• IEC (intestinal epithelial cells) – those in the GI tract (aka barrier, aka mucosa, aka epithelium etc)

GI tract secretes IFN to destroy infection

• Epithelium secretes type I and III interferons (IFNs) to kill virus.

Enterovirus B eliminated successfully by IFN

• Type III IFNs exert a potent antiviral activity against Coxsackievirus B.

Coxsackie BLOCKS IFN III (lambda)

• But Coxsackie B evades host’s immune response in the intestine by preventing type I and III IFN expression in epithelial cells
• CVB cleaves proteins in infected intestinal epithelial cells, blocking IFN III expression.
• Thus, evading immune response

Peginterferon lambda (IFN III) to the rescue

• Interferon-Lambda: A Potent Regulator of Intestinal Viral Infections

 

[nerd]

IFN III just seems to combine the mechanisms of IFN I and II on a cellular level.

But the difference in organ expression is an interesting aspect. IFN type II don't seem to be much different from IFN type III (10.1371/journal.pone.0178993).

The question is if it's IFN type I or II response that is generally lacking in CFS/ME patients. I have elevated IFN type I and a HLA-DR1 genotype that inhibits IFN gamma response. So, in my case, I assume that IFN gamma would be more helpful and IFN gamma has a similar expression in the different organs. The advantage of IFN gamma is that it is better understood and many affordable options of its induction are available.

 

[Hip]

The question is if it's IFN type I or II response that is generally lacking in CFS/ME patients.

It is possible interferon may be hampered in those with chronic non-cytolytic enterovirus because in this non-cytolytic form of the virus, a small part of the viral genome gets deleted, and it is that very part of the genomic RNA that interferon-induced proteins may attach to, in order to disable this viral RNA. This has not been proven, but it is a possibility.

By removing this "X marks the spot" target in the viral RNA, these interferon-induced proteins (called Ifit1) do not know how to disable the viral RNA.

This theory could explain why when enterovirus ME/CFS patients are given 3 months of interferon alpha + interferon gamma combined treatment, although many dramatically improve, they tend to relapse back into ME/CFS 4 to 14 months later (typically after a heavy bout of exercise). This is what Dr Chia found.


If the deletions in non-cytolytic enterovirus's RNA genome confer resistance to interferon, it may be that even after 3 months of interferon therapy, enough enterovirus remains in the body to later re-seed a new infection.



These deleted regions of the enterovirus RNA genome could also explain why the body itself is not able to clear these non-cytolytic infections.

 

[sometexan84]

It is possible interferon may be hampered in those with chronic non-cytolytic enterovirus because in this non-cytolytic form of the virus, a small part of the viral genome gets deleted, and it is that very part of the genomic RNA that interferon-induced proteins may attach to, in order to disable this viral RNA. This has not been proven, but it is a possibility.

By removing this "X marks the spot" target in the viral RNA, these interferon-induced proteins (called Ifit1) do not know how to disable the viral RNA.

So does this mean you do not believe the following...?

• 2Aprotease of coxsackie cleaves MDA5 and MAVS, leading to inhibition of IFNb and type-III IFN

 

[Hip]

So does this mean you do not believe the following...?

• 2Aprotease of coxsackie cleaves MDA5 and MAVS, leading to inhibition of IFNb and type-III IFN

No doubt the actions of 2A play a role in protecting CVB from immune attack too. CVB uses a number of immune evasion mechanisms the thwart the immune response. I've collected various studies looking at the different immune evasion tactics of CVB (this virus simultaneously uses several known immune evasion mechanisms, and probably others that we don't yet know about).

But remember that the immune system is usually able to clear acute enterovirus infections from the body, so in spite of these immune evasion tactics employed by enterovirus, the immune system still wins.

Yet for some reason, the immune system cannot fully clear chronic non-cytolytic enterovirus.


Non-cytolytic enterovirus actually involves very low levels of viral RNA inside cells, with this viral RNA replicating very slowly. So given this infection walks at a snail's pace, the question has always been why isn't the immune system able to clear this virus?

The reason an acute infection taxes the immune system is because the number of viruses in the body grows so rapidly, as the virus replicates in an exponential explosion. So the immune system struggles with the sheer number and exponential growth of an acute infection.

But the chronic non-cytolytic enterovirus case is not like this. The immune system has got all the time in the world to deal with this slow replicating and low level infection; yet the immune system cannot seem to clear it.


To try to explain why the immune system does not seem to be able to clear a non-cytolytic naked viral RNA infection from cells, it was original proposed that the single-stranded (ssRNA) from the virus would join together like two sides of a zip to form double-stranded (dsRNA), which is more hardy than ssRNA, and harder to clear. This indeed happens, as both enteroviral ssRNA and dsRNA has been found in non-cytolytic enterovirus infections.

The dsRNA of non-cytolytic enterovirus has been describes as being like "spores", which cannot be so easily killed. But the fact is that many viral infections create dsRNA as part of their lifecycle, and the immune system is capable of dealing with it. So that dsRNA theory does not seem that viable to me.


A new theory of why the immune system cannot clear this viral RNA from cells was recently proposed by Lévêque and colleagues, who posit that the small deletion in the genome of non-cytolytic enterovirus make it harder for interferon to clear the viral RNA.

But nobody really knows why non-cytolytic enterovirus persists in cells, seemingly impervious to the immune response.

 

[sometexan84]

Yet for some reason, the immune system cannot fully clear chronic non-cytolytic enterovirus.


Non-cytolytic enterovirus actually involves very low levels of viral RNA inside cells, with this viral RNA replicating very slowly. So given this infection walks at a snail's pace, the question has always been why isn't the immune system able to clear this virus?

I hold the belief that persistent enterovirus won't easily be cleared by anyone's immune system. And that it's getting to the point where the enterovirus has settled in, mutated, and become chronic... that's the rare part.

As to why the persistent infection isn't cleared, I still think the main reason is the interferon disruption.

You may not have seen this as it's a 2021, but it's important -
Inhibition of Type III Interferon Expression in Intestinal Epithelial Cells—A Strategy Used by Coxsackie B Virus to Evade the Host’s Innate Immune Response at the Primary Site of Infection?

According to their study, it took 4-6 hours for CVB to cleave the proteins which then blocks interferon. Maybe IFN can normally neutralize infected cells before CVB gets a chance to do its thing.

But if the intracellular immune response is slow enough, then CVB can do its thing.

I know every case is not like mine. But for me this all started w/ the enterovirus, and there were (2) things I did at the time that hinder the innate intracellular immune response.

1) I had multiple corticosteroid shots

2) I was training vigorously. Very intense, long-lasting exercise routines.

Again, I know not everyone got there the same way as me. But I do think a temporarily weak innate immune response is key.

But the chronic non-cytolytic enterovirus case is not like this. The immune system has got all the time in the world to deal with this slow replicating and low level infection; yet the immune system cannot seem to clear it.

And this is exactly why I believe the persistent infection causes havoc. The immune system has gone retarded trying and trying w/out success to clear this thing, and the result is autoimmunity and an immune system that's less capable of taking care of other non-enterovirus infections.

Obviously it's more complicated than that. But I 100% believe that's exactly where the small fiber neuropathy comes from, w/ molecular mimicry involving whatever CVB is using for cell surface binding.

 

[Hip]

As to why the persistent infection isn't cleared, I still think the main reason is the interferon disruption.

This is what also what Lévêque et al have tentatively hypothesized: that the deletions in the non-cytolytic enterovirus genome block the interferon response, making chronic enterovirus more invulnerable to interferon.

The immune system has gone retarded trying and trying w/out success to clear this thing, and the result is autoimmunity and an immune system that's less capable of taking care of other non-enterovirus infections.

Yes, autoimmunity may enter into it also.

Type 1 diabetes, which is linked to a CVB1 or CVB4 infection of the insulin-producing beta cells of the pancreas, is a good model to examine, in terms of investigating chronic enterovirus.

Diabetes occurs because the viral infection is infecting and directly destroying these beta cells, but also because the viral infection appears to trigger autoimmunity, which also starts destroying beta cells.

 

[Pyrrhus]

Right, one reason the side effects were severe is because Type I interferon affects the whole body. But Type III (lambda) works at just the organ barriers (epitheliums), like intestine, lung, etc.

If that's true, then IFN-lambda might not be helpful as it would have no effect on the posited persistent infection in the brain.

Yet for some reason, the immune system cannot fully clear chronic non-cytolytic enterovirus.

And remember that in the case of neurons, it's really not up to the cellular or extracellular immune system- it's up to the infected cell itself. So to be more specific, why can't the intracellullar defenses clear the virus?

The surrounding macrophages can secrete as many cytokines as they like, but the neuron will not apoptose nor will it be phagocytosed.

 

[Martin aka paused||M.E.]

Recently diagnosed with B4 1:480 neutralizationtest... Joshua and me want to kill it with Andrographis

 

[sometexan84]

If that's true, then IFN-lambda might not be helpful as it would have no effect on the persistent infection in the brain.

So does this mean you assume those w/ EV-induced ME/CFS all have the virus in their brain?

 

[Pyrrhus]

So does this mean you assume those w/ EV-induced ME/CFS all have the virus in their brain?

Given the neurological symptoms of ME, the neurotropic nature of enteroviruses, and the immune-privileged nature of the nervous system, that might indeed be a good assumption.

 

[sometexan84]

Given the neurological symptoms of ME, the neurotropic nature of enteroviruses, and the immune-privileged nature of the nervous system, that might indeed be a safe assumption.

Which neurological symptoms are referring to?

You know, an intestinal infection can affect the central nervous system via the gut-brain axis.

I know that enterovirus has been found in brain autopsies of CFS patients. It can certainly find its way there. But it sounds difficult, and rare, even for us.

 

[Judee]

So does this mean you assume those w/ EV-induced ME/CFS all have the virus in their brain?

I know that enterovirus has been found in brain autopsies of CFS patients. It can certainly find its way there. But it sounds difficult, and rare, even for us.

I do wonder if we don't have leaky brain where the BBB is not as intact as it would be in a healthy person allowing more of these pathogens to cross.

I get a swollen brain feeling an awful lot.

 

[Pyrrhus]

I do wonder if we don't have leaky brain where the BBB is not as intact as it would be in a healthy person allowing more of these pathogens to cross.

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.

This retrograde axonal transport can transport enteroviruses from the intestines to the brain via the autonomic nerves that control the intestines, from the skeletal muscles to the brain via the motor nerves that control the skeletal muscles, or by following other nerve pathways.

This retrograde axonal transport was demonstrated most clearly in a now-classic experiment described by Racaniello in a 1992 paper:


Poliovirus spreads from muscle to the central nervous system by neural pathways (Ren and Racaniello, 1992)
https://pubmed.ncbi.nlm.nih.gov/1326581/

In this classic experiment, Racaniello and Ren first developed a humanized mouse model of poliovirus, which is the best studied enterovirus.

Then they injected the virus into the mouse's foot and watched over the span of a few days as the virus first affected the muscles in the foot, then the virus spread to the lower section of the spinal cord, then the virus spread to the upper section of the spinal cord, and finally the virus spread to the brain.

Then they repeated the experiment, but this time they first severed the spinal cord of the mouse. In this case, the virus first affected the muscles in the foot, then the virus spread to the lower section of the spinal cord, but the virus never spread to the upper section of the spinal cord, and the virus never spread to the brain.

You know, an intestinal infection can affect the central nervous system via the gut-brain axis.

That is quite true indeed.
But, in this case, an intestinal infection can also invade the central nervous system via the gut-brain axis.

 

[Hip]

I know that enterovirus has been found in brain autopsies of CFS patients. It can certainly find its way there. But it sounds difficult, and rare, even for us.

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.

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. Herpesvirus brain infections are easier to detect in the CSF.



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.

Perhaps there are some other factors involved, such as for example the triggering of autoimmunity. Or it may be that ME/CFS appears when there is an unusual immune response to this muscle or gut infection, like an immune response which is excessively inflammatory (immune priming theory of ME/CFS).