Do you believe that “viral persistence” is the cause of ongoing MECFS and LC?

They may be yet to find million new things about virus, I don't know. The problem with any old/new findings about virus is that they don't explain anything other than fatigue, never mind making any testable prediction. (Well, ok, some did predict that antivirals would be effective and failed the test). Frankly, I don't see how virus can explain PEM and that's where my objection to viral theories is centered on: no virus theory I know of even tries to explain PEM.

 

It might be true for a small number of ME/CFS cases, but it is not true for the persistence of LongCOVID.

 

I'd understand saying it's unlikely, but I don't see how you can be sure that viral persistence doesn't cause long COVID. We're continually seeing new evidence of SARS-CoV-2 antigen persistence as technology improves. How can you be sure, for example, that we won't eventually find something like 100% of LC and 0% of controls have the virus in one specific region of the brain where it can cause these symptoms?

 

The immune system deliberately preserves antigen fragments for years, that is how we maintain serological (antibody) responses.

If there is viral infection, and it is not 100% dormant (true dormancy is only possible for a few viruses and it isn't actively causing disease when dormant either), there will spillover of viral RNA into circulation and this can be detected.


Mouse models show that antigens are captured and maintained for years.

"Follicular dendritic cells: dynamic antigen libraries"
https://www.nature.com/articles/nri3689

 

This is interesting. No live virus has been found in tissue without spilling into blood? If the virus was in the brain, where SARS-CoV-2 is known to be able to replicate, I'd think it'd be less likely for this to occur, given the BBB.

 

I hope we get a small brain autopsy study into people with Post-COVID ME/CFS with atleast 4 years since last COVID infection.

It would tell us if all this hype is really worth it, or if we can put the persistence theory to rest once and for all.

My personal hunch is that the development of ME/CFS will be associated with RNA fragments and perhaps in some cases minor persistence lasting longer than the average, setting off some problematic feedback loop, but that in no means does any virus have to be persistent for someone to have ME.

 

What about this:

Energy request of active immune cells (2006, Endocrinology)

References:
6: Endotoxin-induced enhancement of glucose influx into murine peritoneal macrophages via GLUT1 (1996, Infection and Immunity)

7: Tumor Necrosis Factor-α Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation (2005, Pathophysiology)

 

Though this hypothesis of exertion taking energy away from immune cells assumes that the immune system is using every bit of energy available to it, and something like reading can divert the limited energy reserves away. It'd be weird if there wasn't plenty of energy buffer available for immune cells, since we know there's plenty of buffer in other exertions, at least in some people with ME/CFS (e.g. relatively little exertion causes me PEM, but theoretically I could physically go run a mile or walk all day). So something complicated would have to be broken, not just a one to one energy steal.

 

This was a while ago, but what do you mean by reactivation of immune responses? That the immune system has become more sensitive or that it overreacts to normal things?

I believe I remember reading something about how the innate immune system halts the energy production in cells for the first few days of an infection in order to starve the intruders that tries to siphon off the ATP. I might just be making things up, but if it’s grounded in reality it fits nicely with the lower desire to eat as a part of the sickness response.

That being said, appetite loss should probably be more prevalent in ME/CFS if the sickness response is involved?

 

There is a thing called the anamnestic response. (Things are a bit confused because the terms used for different things.) Early on in antibody studies by virologists it was noted that antibody levels to things you had met before would rise when you met another different infection. So if you had had chicken pox and met measles you would get a rise in antibody level to measles but also a bit of a rise in antibody to chickenpox. The same thing may occur for T cells but it is much more difficult to measure.

 

I think that is oversimplified popular science. In fact the commonest innate response is fever, which by definition is driving cells to burn more energy and heat you up.

 

So slightly higher antibody levels for X might not indicate an infection with X or reactivation of X, but an infection with Y?

 

Yes, exactly.
Anamnestic strictly speaking means 'non-memory' or something along those lines. I think originally it was used as a general term for rises in antibodies to anything other than the infective agent used as challenge - whether or not there was a past history of the 'bystander' infection.

 

Checking the literature, it seems that one idea for anamnestic is that if Y is a bit like some previously seen X you get a stronger response to Y than if you had not seen X, but that is not how the terms generally used in the 1970s when I learnt immunology so far as I can remember.

Whatever, you can get rises in antibodies as bystander effects.

 

I certainly believe in persistence of borrelia in late stage Lyme and that the Germans sensibly call this "Borreliose mit chronischem Verlauf/course" whereas many English speakers throw a hissy fit at the thought and shout "woo" or invoke BPS according to taste. Some have more informed critiques, of course. The question in Germany is about correct diagnosis but the idea of persistence in some cases is broadly accepted. May be true of ME triggering agents.

Whether long term Lyme is in any way ME is another matter, but normal 2 day CPET tests suggest that LC does not show 2 day "antitraining" of ME cohorts so persisting virus in LC would not necessarily suggest anything about ME (though it might).

 

I personally don't hold much faith in "energy diversion" theories since abnormalities in ATP production in ME/CFS have been found in various cell types, even when cultured or otherwise processed after a long period of time outside of the body. Those cells didn't have to "compete" with any other bodily system for the substrates of energy production.

It's also worth noting that it's absolutely possible to have innate immune activation in the absence of any pathogenic trigger--there have been several neat studies showing that simply by inhibiting oxidative phosphorylation in macrophages you can induce a pro-inflammatory phenotype. It's also common to induce a pro-inflammatory phenotype experimentally in macrophages by lipopolysaccharide exposure. Many immune cells, but especially myeloid cells, have bi-directional regulatory relationships between energy metabolism and immune response pathways.

I have a feeling that flu-like symptoms in PEM are more likely mediated by innate immune cells responding to something that occurs when globally impaired ATP production cannot match the level needed for an activity in the moment. There are lots of candidates here--increased ROS production, increased reliance on beta oxidation altering lipid metabolism, an upregulation in glycolysis if OxPhos is inefficient etc. And there's likely a time component of how long it might take those pro-inflammatory cells to return to a non-inflammatory phenotype after the original insult which may explain the duration of PEM after the initial overexertion.

To me it's an Occam's razor situation--there could be some level of viral reactivation happening in every case of ME/CFS, but if you can explain the key features of ME/CFS without viral reactivation, the simpler explanation prevails.

 

Also, I think it's possible to have an initial systemic shift in energy production caused by a virus (or the subsequent immune response) that persists even after the virus disappears. The body changes its own energy metabolism pretty dynamically in response to a whole host of issues ("euthyroid sick syndrome" in response to acute infection or bodily trauma is just one example). All you need is one mutation that functionally inhibits any part of that regulatory network, and you have a body that is stuck in a partial state of altered virus-response metabolism long after the virus has been cleared. And if that's the case, it's likely different mutations in different people

 

Chronic but not acute sarcoidosis shows lowered oxphos, so interesting what you say. Sadly this area of sarc is not widely appreciated as a possible cause of fatigue and of inflammation which may cause further fatigue.

 

Do we really have good evidence for inadequate ATP generation in ME/CFS? As I understand it Audrey Ryback's attempt to show altered metabolism did not replicate previous findings. Metabolic behaviour of peripheral blood cells is probably uninterpretable because circulating cells are not normally doing much anyway and there may be shifts in populations in terms of ageing etc. for secondary reasons. If people with ME/CFS do about as well as normal people on a first time CPET then it seems unlikely that symptoms have much to do with a major energy deficit.

Not sure we have evidence of 'mutations' unless of course we are talking of somatic mutations in Ig genes in antibody producing cells, which would be very possible.

 

Unable to link specific studies now as I don’t have my laptop today and am on my phone, but you’re right that it’s inconsistent across studies. For me, despite individual inconsistencies in studies, I see a strong global pattern pointing specifically to impairment of OxPhos and concurrent upregulation of glycolysis, glutamine metabolism, and beta oxidation as compensatory mechanisms. The upregulation of compensatory mechanisms could explain the appearance of normal function in short instances, but overall failure to maintain endurance over longer periods of time as well as deficiencies in tissues that preferentially use OxPhos under certain conditions (skeletal muscle, heart, certain parts of the brain) or that rely on OxPhos for phenotypic regulation (e.g. macrophages).

Off the top of my head we have @DMissa’s study showing reduced complex V activity in immortalized lymphoblasts, Booth et al., Lawson et al. (and at least one other study that escapes me) showing upregulated baseline ATP production from glycolysis, and several metabolomic studies showing differences in beta oxidation, glutamine and urea cycle metabolites (please correct if I’m misremembering any details since I don’t have all the papers in front of me). Furthermore, you have evidence of reduced steroid synthesis in androgenic steroids, progestins, corticosteroids, and bile acids (Germain et al. and my recent LC study Gabernet et al.), which are all dependent on conversions of cholesterol by mitochondrial NADPH-dependent enzymes. To me, this points to redox imbalance in adrenals, gonads, and liver at the very least, and is exactly what you would expect as a downstream, long-term byproduct of impaired OxPhos. You also have potential signs of redox imbalance in sphingolipid abnormalities (which has shown up as both upregulated and downregulated but strongly in either case—would have to be explained in terms of differential use of serine metabolism as a compensatory redox regulator) and the frequency of alcohol intolerance in ME/CFS (ethanol breakdown requires cytosolic reducing agents).

Granted, some of these findings could be only specific to the cell types studied. And, in the case of Lawson et al. I strongly suspect there is something in the cell preparation that actually lead to normal mitochondrial function in their PBMCs. In terms of the plasma metabolomics studies, it is unlikely to just be one pathogenic celltype that is driving those metabolic signatures, pointing to a more global deficit.

Obviously this is only speculation at this point and would need to be investigated in more detail. I’m currently working on doing exactly that. As it stands, I completely acknowledge that the exact evidence is inconsistent, though I think there is merit in the fact that several different findings across studies can all be linked by a singular mechanism.