A Murine Model of ME/CFS: Shouldn't this be Possible?

[Hip]

Mouse Model of ME/CFS

I was thinking that a murine model of ME/CFS might be possible. Such a model could significantly speed up research into the pathophysiology of ME/CFS, since murine nervous systems could be dissected and closely examined for viral infection, etc, and it should then be possible to work out exactly the areas in the brain are compromised in ME/CFS.

One question with such a murine model is how can you know that a mouse has ME/CFS?

Well, since ME/CFS has two very characteristic symptoms of cognitive dysfunction (brain fog) and post-exertional malaise (PEM), mice that have been injected with viruses and bacteria in order to precipitate ME/CFS could be put through simple maze tests and so forth to see if the mice have acquired the these two characteristic symptoms.

Brain fog involves cognition dysfunctions such as poor short-term memory, poor working memory, and frequent miscategorisation of objects or stimuli (like answering the phone when the doorbell rings!). Even in mice, these types of basic cognition difficulties should be measurable and quantifiable through standardized maze and similar tests. Although brain fog also occurs in other diseases as well, the brain fog of ME/CFS is quite unique in that it worsens significantly as a result of post-exertional malaise, and this fact should be easily verifiable in mice, simply by pushing these mice through lots of exertion, and noting their increasing brain fog and declining cognitive performance on maze tests.

Once you have shown that the mice have quantifiable brain fog which also significantly worsens after exertion, you should be able to conclude with confidence that these mice have ME/CFS.

One could presumably use this murine model of ME/CFS to learn what types of combinations of microbial infections can precipitate ME/CFS in the first place.


For example: from the human statistical data on ME/CFS, we know that prior conditions/infections like IBS/SIBO, chronic recurrent urinary tract/kidney infections, interstitial cystitis and overactive bladder are common in ME/CFS patients, and thus may conceivably predispose a person to acquiring ME/CFS. But there is no direct proof that these prior conditions/infections do play a causal role in ME/CFS; all we know at the moment is that these prior illnesses are statistically co-morbid conditions of ME/CFS.

Thus it would be very interesting to see if mice too, if given such prior conditions like a chronic kidney infection, would then more easily develop ME/CFS when later given a enterovirus or herpesvirus infection.

This is one example of how a murine model of ME/CFS could provide invaluable data on the etiology of this disease.

 

[Snow Leopard]

I guess the problem is that there are many ways to induce such fatigue and so the the "chronic fatigue" that the mice have might have different pathology to that of humans.

Actually, this is a problem with CFS research in general, this condition might literally be a combination of all possible unknown causes of fatigue - from multiple/novel autoimmune disorders, to chronic viruses (and unusual immune reactions to those viruses) to rare mitochondrial to pain/fatigue signalling disorders.

 

[Hip]

Actually, this is a problem with CFS research in general, this condition might literally be a combination of all possible unknown causes of fatigue - from multiple/novel autoimmune disorders, to chronic viruses (and unusual immune reactions to those viruses) to rare mitochondrial to pain/fatigue signalling disorders.

I tend to agree: ME/CFS may only arise when you have several pathogens / ill-health conditions in your system, with ME/CFS appearing as a kind of "straw that broke the camel's back" phenomenon, as a result of the additive negative effects of these individual conditions. That is, perhaps the triggering respiratory virus that people often report precipitated their ME/CFS was the final straw on an already overloaded body.

Though this is where a murine model of ME/CFS may be really useful: to work out the circumstances that leads up to the straw breaking the [STRIKE]camel's[/STRIKE] mouse's back. For example, let's give a mouse some gut dysbiosis first (via some virulent bacteria), then add a bit of leaky gut, then give the mouse a urinary tract infection, etc, and after all that, then introduce a potent respiratory virus to the mouse (like coxsackievirus B). During this "straw loading" process, we will check to see if and when ME/CFS arises.

There may well be more that one "formula" of causal factors that leads to ME/CFS; a murine model may help explore the different causal factor formulae that lead to ME/CFS.

 

[Hip]

I should point out that there is a murine model available for coxsackievirus B chronic myocarditis (see the links below).

The intracellular infections of coxsackievirus B found in chronic myocarditis are very similar to the intracellular infections of coxsackievirus B found in chronic fatigue syndrome. So setting up a murine model for coxsackievirus B driven ME/CFS should be quite straightforward provided you can introduce irritable bowel syndrome, leaky gut, urinary tact infections, etc, into the mice, which may be the necessary prior conditions for ME/CFS to later be triggered by a coxsackievirus B infection.


A mouse model of coxsackievirus myocarditis
Coxsackievirus-induced chronic myocarditis in murine models
An in vivo model of autoimmune post-coxsackievirus B3 myocarditis in severe combined immunodeficiency mouse

Coxsackievirus-induced myocarditis in mice: a model of autoimmune disease for studying immunotoxicity
Transgenic mouse model for echovirus myocarditis and paralysis
Therapy With Immunoglobulin Suppresses Myocarditis in a Murine Coxsackievirus B3 Model : Antiviral and Anti-inflammatory Effects

 

[Tony Mach]

I think at the current state of knowledge about the cause(s) AND mechanisms of ME/CFS it is folly to try to create a mouse model with the patient reported symptoms being barely the only thing that there is agreement upon, how can one create a mouse model? I think one could create something in mice that looked like ME/CFS, but is it ME/CFS?

There is a lot of research going on (compared to one year ago) with regards of what are the mechanisms and how can we test for them, plus maybe Lipkin can find the pathogen(s) maybe a mouse model makes sense after the results of the current line of inquest come in.

 

[alex3619]

Hi, there have been "attempts" to create a murine model. A number of studies have exhausted mice from exercise. Thats chronic fatigue, right? The problem is a model has to be specific to the pathophysiology, and we are only just starting to understand that pathophysiology. Bye, Alex

 

[kaffiend]

This is a good article that is somewhat related.

http://www.wired.com/magazine/2011/12/ff_causation/all/1

"Because scientists understood the individual steps of the cholesterol pathway at such a precise level, they assumed they also understood how it worked as a whole. This assumptionthat understanding a systems constituent parts means we also understand the causes within the systemis not limited to the pharmaceutical industry or even to biology. It defines modern science. In general, we believe that the so-called problem of causation can be cured by more information, by our ceaseless accumulation of facts."

 

[Hip]

with the patient reported symptoms being barely the only thing that there is agreement upon, how can one create a mouse model? I think one could create something in mice that looked like ME/CFS, but is it ME/CFS?

I suggest by basing the mouse ME/CFS model inclusion criteria on agreed-upon reported symptoms; and specifically, on the two most common and characteristic ME/CFS symptoms: post-exertional malaise PEM and cognitive dysfunction CD. But more importantly, the mouse model inclusion criteria would also be based on the dynamic interplay between PEM and CD: that is, in ME/CFS, we know PEM dramatically increases CD.

These would be the 3 inclusion criteria for mice in the murine ME/CFS model:

(1) The mice must have CD
(2) The mice must have PEM
(3) PEM must dramatically increase CD

In fact, these 3 simple mouse criteria may well be better than the Oxford criteria for human ME/CFS! The Oxford criteria are criticized for being too vague, and possibly including depressed people that don't have ME/CFS into the ME/CFS study sets. Whereas the 3 simple mouse inclusion criteria may be better than the Oxford criteria in terms of separating ME/CFS cases from depression cases. Exercise almost invariably improves depression symptoms; whereas exercise makes the CD symptoms worse in ME/CFS, at least in the day or two after exercise, so mouse inclusion criterion (3) would at least distinguish ME/CFS from depression.

 

[Hip]

Hi, there have been "attempts" to create a murine model. A number of studies have exhausted mice from exercise. Thats chronic fatigue, right? The problem is a model has to be specific to the pathophysiology, and we are only just starting to understand that pathophysiology. Bye, Alex

If the studies you are thinking about just exhausted healthy mice from exercise, that's not considered chronic fatigue, nor chronic fatigue syndrome, nor myalgic encephalomyelitis.

Exhaustion from exercise in the healthy is not the same as PEM (post-exertional malaise) in ME/CFS.

 

[Hip]

This is a good article that is somewhat related.

http://www.wired.com/magazine/2011/12/ff_causation/all/1

"Because scientists understood the individual steps of the cholesterol pathway at such a precise level, they assumed they also understood how it worked as a whole. This assumptionthat understanding a systems constituent parts means we also understand the causes within the systemis not limited to the pharmaceutical industry or even to biology. It defines modern science. In general, we believe that the so-called problem of causation can be cured by more information, by our ceaseless accumulation of facts."

A good article. I used to be interested in the philosophy of science (before ME/CFS brain fog shrunk my brain to a pea). But I still do wonder how medicine as a whole is going to get around this very unsatisfactory and lengthy two-step scientific process of:

First finding the factors that are associated with a given disease (which takes a long time anyway).
And then trying to work out: which of these factors play a causal role in the disease; which factors are a consequence of the disease; which factors are contingent upon other factors before they become causal. This second step is extremely difficult to do.

This above scientific process is the logjam of all medical research. If someone could devise a better scientific method in this area, the logjam may be cleared and the etiology of many more diseases, not just ME/CFS, might be resolved.

One approach I think might work well (in the future) is to monitor all the pathogens and toxins that each individual in the population is exposed to on a day by day basis. Imagine if, in the future, we could all wear a simple wristwatch type device that would automatically monitor our blood, and note when new antibodies appeared to any infection we picked up, and note any toxin we were exposed to; then this would provide an incredible database that would help us sift out causal from non-casual factors of diseases that later appear in individuals.

The above logjam is mainly due to the fact that we don't have good timeline data on a disease. We can analyze the disease data from the patients in front of us, but we have very little history data on each patient to make use of. A device like the wristwatch monitor described could change all that.


This is an article I enjoyed: Equations that Spell Disaster: Researchers are pinpointing the factors that combine to produce complex diseases. In this article, the research on a Crohn's disease murine model I thought was particularly illuminating. It was found that Crohn's appears only when three factors are all simultaneously present: a norovirus infection (but it must be the CR6 strain of norovirus), a certain Atg16L1 gene allele, and exposure to the DSS toxin. When you get all three of these factors together, Crohn's is triggered. Otherwise not. That is a pretty precise equation.

It would be good to have similar research on a murine model of ME/CFS, so we can know which combinations of causal factors lead to ME/CFS in mice.

 

[alex3619]

Hi Hip, no, they considered it a mouse model of chronic fatigue syndrome. There have been several such studies over the years. I don't agree with them, I think the approach is bogus, which was my point. Bye, Alex

 

[Hip]

Hi Hip, no, they considered it a mouse model of chronic fatigue syndrome. There have been several such studies over the years. I don't agree with them, I think the approach is bogus, which was my point. Bye, Alex

I think I have found one of the mouse ME/CFS models you are talking about. This study just got healthy mice to swim, and assumed that in their lethargy and immobility after the bout of exercise was like the PEM of chronic fatigue syndrome, which is which is a very flimsy assumption, to say the very least:

http://www.ncbi.nlm.nih.gov/pubmed/12639396

However, I just found two other studies where more plausible mouse ME/CFS models were set up. So it seems there are some half-decent ME/CFS mouse models around after all.

This study injected the mice with lipopolysaccharide (LPS) and Brucella abortus antigen in order to precipitate a brucellosis type ME/CFS condition:

http://www.ncbi.nlm.nih.gov/pubmed/20537729

And this recent study infected the mice with murine gammaherpesvirus 68, a virus similar to Epstein-Barr virus, and then later injected the mice with LPS:

http://www.ncbi.nlm.nih.gov/pubmed/21272632

The gammaherpesvirus-infected mice showed an exacerbated response to LPS, compared to a control group of uninfected mice that were also injected with LPS.