Everything you always wanted to know about non-cytolytic enterovirus but were too afraid to ask

I thought I'd be the first to take advantage of this new MEpedia sub-fourm, by posting a link to a new MEpedia article I just completed today, which is found here:

Non-cytolytic enterovirus — MEpedia article



This MEpedia article is a (hopefully) accessible introduction to non-cytolytic enterovirus, the aberrant and mutated form of enterovirus found as a persistent infection in the tissues of many ME/CFS patients.

Chronic non-cytolytic enterovirus infection is an important subject, because many doctors even today are taught that enteroviruses do not form chronic infections, and thus the concept of an enteroviral infection that persists in the muscle, digestive tract and brain tissues of ME/CFS patients does not quite fit their training (even though numerous studies have demonstrated this to be the case).

Through the work of Professor Nora Chapman and her colleagues, we now understand the mechanism of enteroviral persistence in the tissues: in brief, her research demonstrates that that certain mutations which enterovirus acquires in the host during the acute stage of infection can transform it into a pathogen with a radically altered lifecycle, and a pathogen that can form persistent infections in the host tissues.

Prof Chapman's identification of the mechanism behind non-cytolytic enterovirus has import not just for ME/CFS, but also for several other diseases in which persistent enterovirus infections of the tissues are found, including chronic myocarditis, dilated cardiomyopathy (the reason for around 45% of all heart transplants), type 1 diabetes, motor neuron disease, Sjogren's syndrome and Parkinson's disease. The working hypothesis is that the aberrant non-cytolytic form of enterovirus may be a cause for all these illnesses.

Thus the medical significance of non-cytolytic enterovirus goes beyond just ME/CFS.



Anyway, if you get a chance to have a look at this article, I'd be pleased to hear any feedback or suggestions.

Was it reasonably easy to grasp, or were there certain concepts or certain areas that were hard to follow in the article? The aim is to make the subject accessible to a lay audience.

I tried to write the article so that the easiest to understand sections are first, and the more difficult material appears later. So reading say the first four sections should be relatively easy, and give an overview and basic understanding. Then if you want to delve deeper, the subsequent sections will take you in further. But the first 4 sections may provide an adequate overview for most people.

I wanted to try to write an accessible article on non-cytolytic enterovirus for a long time, so I am thankful to @JenB for the encouragement to do some editing on the enterovirus pages of MEpedia, which spurred this article into existence.

 

https://me-pedia.org/wiki/Non-cytolytic_enterovirus

 

By the way, if anyone wants to have a go at adding a few pearls of their ME/CFS knowledge to MEpedia pages, it is pretty straightforward. You don't even need to set up an account (although it's better to do this in the long term).

On any MEpedia article, just press the Edit button at the top of the page, and this launches the visual editor, which works like a simple word processor. Then type in your text, and press Save Changes to save the page when complete. That's it.

The process of adding study references to your text is also simple and streamlined: just click on the Cite button at the top of the visual editor, select Automatic, and then paste in the web address (URL) of your study, or alternatively paste in the study PubMed ID or DOI, and the study reference that look something like this: [12] is automatically generated and inserted at the location of your text cursor.

You can try this out on any MEpedia page by launching the visual editor, and typing in a few things just for practice, or adding a study reference for practice, and then afterwards closing the webpage in your browser without pressing the Save Changes button, whence your changes will be discarded. Anything you type in to the page is only saved if you press the Save Changes button.

 

This is all stuff I know nothing about, and I'm too intimidated to try to learn, but it looks like a lot of work went into it! Thanks to @Hip and everyone else contributing to MEpedia.

 

That was my reaction, too. Thanks @Hip.
I know nothing about this topic, and it's a rather complicated one, but you managed to explain it clearly.
Must have been a massive amount of work!

 

Yes, it sort of totally took over my life for the last two weeks! But there is so little accessible information out there about non-cytolytic enterovirus, even though several researchers think this viral aberration may be a major cause of ME/CFS.

 

OK, my knowledge of biology is basic, really basic, but I found it fascinating. I had to look up "cytolytic", and of course it made more sense then. I started to read it late last night, but stood no chance. So here are my comments as I read through it.

First of all, just to check my memory about polio being an enterovirus, I did Google "enteroviruses" and read the interesting line that "cell mediated immunity may actually increase inflammation and thus worsen clinical sequelae such as myocarditis without clearing the infection." Once I'd worked out that "sequelau" actually meant what I suspected it would, that sentence seemed quite important to me. It's frustrating when you have to keep looking up technical terms that have simple meanings. Is it possible to have a drop-down box appear if you hover your mouse over certain words, as opposed to a link?

Then I discovered that you already did that, and decided that I am a naive technological fool masquerading as someone who has got to grips with the basics. I could still do with one for "non-cytolytic" though.

One thing that strikes me early on is that no time scales are mentioned. Is the transmutation quick, or are we talking years? I'm guessing, that as the non-transmuted form provokes an immune response, the transmutation must take place within that period of response. (I'm trying to match it with rapid onset of ME virtually as soon as the infection starts up, combined with, is it Lipkin's comment, that ME is different after 5 years or so.)

I'm going to pass on understanding the details of ss and dsRNA, but I get the gist of it. (see note 4 paragaraphs later)

Interesting bit about its replication in quiescent cells. Very well explained.

"The deletions range from 7 to 49 nucleotides in length".... under the diagram of the creation of noncytolytic etc. In comparison with how many in the entire strand, just out of curiosity, and trying to get an overall image? (I found the answer at the end!)

The steroid link is interesting.

Under "summary characteristics" you mention "double-stranded RNA", but it was only then that I realised what ss-RNA and ds-RNA stood for! It could just be that I'm a dozy idiot, or it could be that I'm so used to being overwhelmed with acronyms and technical terms, I tend just to accept them as they are and not actually think about what they could mean.

What is the difference between cytolytic and cytopathic?

The brief history was very illuminating!

I didn't work through the "important studies".

Note on defective interfering viruses - again interesting.

I must confess, when I got to the instruction "See also" my brain rebelled and decided it was time to take the dog out for a walk.

But that is one of the most fascinating accounts I have read for a long time since first hearing Betty Dowsett talk about enteroviruses and polio. Thank you.

And there wasn't a single phrase or grammatical oddity that threw me.

I think it is highly desirous
We read of the enterovirus
It seems they can dwell
Unseen in each cell
For years while they slowly rewire us

 

Cytopathic - kills cells
Cytolytic - kills cells by rupturing the cell membrane
[I wanted to say "with tiny swords" - but that's not strictly accurate]

 

Thanks so much @Graham for reading it and giving feedback, it's much appreciated.

That's a very good point. I'll add some info about timescales. I don't think the exact timescale of conversion to the non-cytolytic form is known, but in myocarditis it is certainly less than 28 days.

In enterovirus heart muscle infections (myocarditis), if you are unlucky enough to have your acute enterovirus infection not clear up within a few weeks, and for it to transform into a non-cytolytic infection, by day 28 of the infection all the acute lytic virus will have disappeared from the heart, and just non-cytolytic enterovirus is left, which then takes over from that point, causing a chronic infection. That's what happens in mice experiments anyway.

So within the first 28 days of infection, that's when non-cytolytic enterovirus emerges. Whether there might be different timescales in other diseases or other infected organs (such as the brain) I am not sure.

Perhaps it might be an idea to define ssRNA (single-stranded RNA) and dsRNA (double-stranded RNA) more than once in the article. These acronyms are defined towards the beginning of the article, but of course it is quite a long article, and people often jump into articles at various points, at whichever section is most relevant for them, so I guess it would not do any harm to redefine these once or twice.

Good point, it does mention the total size of the coxsackievirus B genome (7,400 nucleotides) later in the article, but it may be an idea to mention this earlier at the point you mention.

They mean similar things: cytolytic means destruction of a cell by rupturing it (cyto means cell, lysis means rupture of a cell); cytopathic refers to something which observably damages a cell, typically cell rupture.

Viruses will often rupture and kill a cell during viral replication, but this aberrant form of enterovirus found in ME/CFS does not rupture and destroy the cells it lives in, hence the names non-cytolytic and non-cytopathic, which are synonyms in this enterovirus context.

Perhaps I should add the above explanation to the article.

I could I guess add a glossary at the end of the article, where terms like dsRNA and non-cytolytic are defined.

That is truly brilliant, @Graham! That limerick should have an MEpedia page just on its own!

 

Had a scoot around at some of your other work @Hip - and came across this: Prozac inhibits enterovirus replication
wow.
(although unfortunately not replicated in EV-D68 in mice)

 

Thanks @Hip . I did understand that point clearly as I read it, and as I said, I was writing down comments as I read it as they occurred to me. Actually, you did cover almost everything, it was just that these things occur to me then niggle away and disrupt my concentration, so if there are any poor sods like me out there, perhaps an earlier note would help.

I don't think a glossary at the end is necessary. Most of the terms were self-explanatory or had drop-down links. You might end up creating a monster of a task. Although I can think like a scientist, I can't remember terms and details that well, so if I'm happy, I'd guess that many people would be.

I'd like to send a link to it to Jane Colby, who worked with Betty Dowsett for many years: I'm sure she would find it useful. I'd also like to try it out on a couple of friends with ME who are pretty bright, but not well up on ME research. Is that OK? I'll give you feedback if anything useful comes up.

If you want to use the rhyme, feel free. No attribution necessary.

I really am very impressed, and those who know me well will tell you that I don't hand out compliments easily!

 

I know exactly what you mean: especially with brain fog, if you get bombarded with too many undefined terms, it interrupts the natural flow of reading, and then you can lose interest, or you end up putting the article away for another time.

It would be great to get feedback from your ME friends.

 

This post and several following posts have been moved at @JenB's request from this thread.

Regarding the non-cytolytic enterovirus article in specific, the first passage reads:

So IMO from reading this passage it should already become clear to the reader that the article discusses the findings and mechanisms of non-cytolytic enteroviruses in mentioned diseases, but does not debate the stronger and more specific argument that non-cytolytic enteroviruses necessarily would cause these diseases. Even if enteroviruses are found frequently in these diseases, it could be some other underlying factor that causes the disease and predisposes to these chronic enterovirus infections as well. The MEpdia article specifically links to skeptical studies that have found no causative association as well, for example:

 

I personally would not mind at all including a qualifying statement like that, assuming it is true that most of the research community do not view non-cytolytic enterovirus as likely to have any disease-causing effects (which I expect it might well be).

However, one problem I can see with including such a statement is the need to find a reliable source which has already polled the research community about their views on non-cytolytic enterovirus. Because if we are going to say "most of the research community don't think much of the non-cytolytic enterovirus hypothesis", then that statement really needs to be supported by a factual source.


The second issue is that I would think nearly all theories or hypotheses about ME/CFS which might get included in MEpedia would probably be met by a certain amount of incredulity from the majority the biomedical research community, because usually scientists are not ready to give credence to other scientists' theories until a strong empirical evidence base accumulates.

So the same qualifying statement would need to be placed at the top of every MEpedia article that details any hypothesis about the pathophysiology of ME/CFS.

That would include the cell danger response hypothesis, the vagus nerve hypothesis, the mitochondrial dysfunction hypothesis, Ian Lipkin's hypothesis of an as yet undiscovered ME/CFS-causing pathogen, the autoimmune disease hypothesis, Dr Lerner's abortive infection theory, Wyller's sustained arousal hypothesis, the corticotropin-releasing hormone receptor 2 up-regualtion hypothesis, the retrovirus theory, the leaky gut involvement hypothesis, the immune priming theory of ME/CFS, the gut microbiome hypothesis, etc.


And the third issue is about the nature of MEpedia itself. Does it necessarily have to follow the rules and principles of Wikipedia medical, which as we know tends not to include any primary studies, relying for the most part on review papers? Or can MEpedia be more open to expounding upon interesting hypotheses, one of which might one day might provide a lead to the correct explanation of ME/CFS?

Given that very little is currently known about ME/CFS pathophysiology, there is very little undisputed factual information that can be included in MEpedia at present; but there are various hypotheses.



But I do agree that there should be a clear distinction made between hypothesis and incontrovertible biomedical fact.

Possibly a simple solution to the issues you raised might be for MEpedia to have a special "Hypothesis Banner" which is placed at the top of all articles which offer hypotheses, ideas, theories and speculations about ME/CFS.

 

I don't think a lot of PWME are going to read it that way. The article does not 'debate' the idea that the virus is causal but it certainly suggests that this is being investigated. What it does not say is that for the vast majority of biomedical scientists in the field the idea that Parkinson's disease or ALS are caused by non-cytolytic virus is too implausible to be worth considering for a whole host of reasons. For myositis the issue was specifically investigated in the early 1990s and the original evidence was found not to hold up.

And the problem is worse than that because, as far as I am aware, most biomedical scientists in the field don't really buy into the idea of non-cytolytic infection of any clinical relevance at all. It is all the speculation of a handful of enthusiasts.

As I have said, I don't want to be a complete wet blanket, but I doubt the people involved in producing MEpedia material are really aware of just how difficult a task this is. The scientific literature is full of rubbish these days. Finding people who can give a genuinely balanced overview is hard. Flagging pages as hypothesis or speculation may help, as a minimum, but the downside is that legitimises including what may be very misleading material.

 

@Hip Great article. I am wondering if this is your leading theory for whats going on in CFS?

 

@Hip

Non-cytolytic enteroviral infections exist. This is not disputed (right?). The question is whether they cause or contribute to any given disease pathology or its symptoms. I think if the majority of the page was just focused on explaining the mechanisms of non-cytolytic infection in an encyclopedic format/tone, you could then have a section called "Role in myalgic encephalomyelitis" or "Role in human disease" (if you want to incorporate literature from multiple fields) where you could then lay out all of the debate + uncertainty. I think this is far better than having the argument (pro or con) set the POV of the entire article.

This approach would be analogous to the "Controversy" section many Wikipedia articles have. This is a useful approach on Wikipedia because then you're not arguing throughout the entire article. What is (more) settled can take up the bulk of the article and what is an open debate can be addressed in a specific section of the page.

OR, you there could be two pages: one for Non-cytolytic enteroviral infection written in encyclopedic format/neutral tone and one that is a "medical hypothesis" page called something like "Enteroviral infection hypothesis" that lays out the theory and examines the evidence for it.

This post probably belongs on the Non-cytolytic enteroviral infections thread

 

We already have this @Hip https://www.me-pedia.org/wiki/Category:Medical_hypotheses

And looks like there's already an Enteroviral infection hypothesis page: https://www.me-pedia.org/wiki/Enteroviral_infection_hypothesis

@Hip we really need to figure out the proper scope of each of these pages so there is not too much duplication:

https://www.me-pedia.org/wiki/Enteroviral_infection_hypothesis
https://www.me-pedia.org/wiki/Non-cytolytic_enterovirus
https://www.me-pedia.org/wiki/Coxsackie_B
https://www.me-pedia.org/wiki/Enterovirus

Remembering that "Main article template" (https://en.wikipedia.org/wiki/Template:Main) is our friend!

(Can a moderator help with moving this post and other posts on this thread that are really about the non-cytolytic EV page to that thread?)

 

Yes that right, there does not seem to be any dispute that non-cytolytic enteroviruses exist; the controversy is whether or not they play a role in the various diseases that they are found. The non-cytolytic enterovirus article focuses mainly on explaining what these viruses are: how they arise, how they replicate and propagate, how they evade the immune response.

The article does not focus much on how they might cause disease, apart from mentioning a few points in passing.

Yes, that makes sense, and there already appears to be a page entitled Enteroviral infection hypothesis. That's where arguments for and against the the enterovirus hypothesis can be included.

The trouble, though, will be finding good arguments against the enterovirus theory. I've never come across any properly argued skeptical views on the enterovirus theory, and I am always interested in a good skeptical view.

I know some people say "Nah, that enterovirus theory ain't gonna work", but that's not really saying anything. A skeptical argument against needs to be just as well constructed and engaged in the details as the pro argument for.

 

Well, and it also needs to be published somewhere. We can't just write out a 'con' opinion as MEpedia really isn't for original writing.

Also @Hip my apologies. I edited the post above.