Let me do a devil's advocate on them, like we used to in the lab on a Friday afternoon after Linda had got a couple of bottles of wine in - the way we got answers, even if dozens of theories lay dead on the floor by the end.
Well I had half a glass of wine earlier, so I'm primed!
And I think we may need to be careful about his broad brush idea of glial cells all around. I may be wrong but I think microglia are found in the central nervous system. In peripheral nerve, like vagus, there will be macrophages around (I am not sure where satellite comes into this - various sorts of 'satellite cell' are something else) but are they microglia? And why should macrophages around a nerve contain organisms rather than macrophages everywhere else? It would not be infection of the nerve, as in Chia's transportation up the axon, because that is inside the nerve. I am finding it hard to get the bits to fit.
Satellite glial cells were a new one on me when I first read the VanElzakker paper, but you can see in
this list of glia that satellite glial cells are a category of glia which are found surrounding neurons in sensory, sympathetic and parasympathetic ganglia. Satellite glial cells are very similar to astrocytes.
Assuming these satellite glial cells can get infected, the question I am trying to work out is why, out all the individuals who catch say an enterovirus or EBV, does the virus only purportedly infect the vagus in a very small percentage of people, who then develop ME/CFS? Is it just random, like the fact that any infection you catch may randomly end up in one of several of its favorite places in the body?
Obviously there is a certain random element, because when for example people catch coxsackievirus B, only a small percentage will develop a heart muscle infection (myocarditis) from it. But in most people, the virus will not touch the heart.
But if there were factors that predispose to vagus infection, then by knowing these, it might help to develop ways to mitigate an existing vagus infection.
In terms of testing for a chronic vagus nerve infection, Michael VanElzakker says post-mortem studies are necessary, but I was wondering whether there may be a way to detect this infection in living ME/CFS patients. One idea I had — and I don't know how technically feasible or sensible this would be — is to use some radiolabeled antibodies that attach to the IL-1β cytokine, and then see if these antibodies congregate in the vagus nerve. If his theory is correct, then you might expect the vagus nerve of ME/CFS patients to show up as a crisp line of radiolabeled IL-1β in PET scans, but not show up at all in the scans of healthy controls. (Although this might not work that well, since secreted IL-1β is free-floating).
Yes, but that is a bit embarrassing because different pathogens tend to differ in where they like to hide. EBV hides in B cells. Brucella hides in sacroiliac joints. Syphilis hides in the aorta, TB in the top of the lung. Polio clobbers anterior horn cells. Absolutely nothing is known to hide in the vagus, despite a century and a half of hard work by pathologists. This is where I think Michael might benefit from reading a 1960s infectious disease textbook.
That is a very interesting objection to the theory!
I performed a bit of a search, and found that herpes simplex I can infect the nodose ganglion of the vagus nerve (ref:
here), but apart from that, I could not find any indications that the vagus can host infections.
So that's not a good start to keeping this theory alive.
However, I cannot see why theoretically the vagus nerve satellite cells, which are like astrocytes, cannot host some low-level infection, such as an intracellular enterovirus infection, that would not necessarily show up in post-mortems and suchlike. The infection may be low-level, but because of extreme proximity to the nerve neurons, the IL-1β released by the infection should robustly activate the nerve and sickness behavior.
Coxsackievirus B has been shown to cause chronic infections in both
human and
mouse astrocytes (which then secrete the appropriate sickness behavior cytokines IL-1β, TNF-α and IL-6); so this virus may well be able to infect satellite cells. Astrocytes have both the CAR and DAF surface receptors, which coxsackievirus B can use for cellular entry.
If all else fails, perhaps we could fall back to the slight variation of the theory that I suggested earlier, which was that instead of the vagus being infected, it may instead be the inflammatory cytokine IL-1β secreted from a chronic enterovirus infection of the stomach which activates the vagus, as this nerve innervates the stomach.
This fall-back theory kind of makes sense, because of course one of the functions of the vagus is to detect any infections in the body via the inflammatory cytokines these infections induce, and then on detection, to activate sickness behavior. So this turning on of sickness behavior because of a stomach infection would be quite run-of-the-mill stuff for the vagus.
Of course, normally you would expect stomach infections to be acute, like a stomach bug that lasts a few days, and the vagus would only turn on sickness behavior for the duration of the acute infection, and then turn it back off once the infection is cleared. But in the case of a chronic stomach infection, the idea is that sickness behavior remains permanently turned on.
An interesting point of comparison is chronic hepatitis C virus infection of the liver. This liver disease has symptoms quite similar to ME/CFS, and presumably its fatigue, brain fog, etc symptoms are sickness behavior manifestations, most likely induced by the chronic IL-1β activation of the vagus nerve that innervates the liver (I checked, and it says
here that IL-1β is involved in the pathogenesis of HCV).
So hepatitis C infection of the liver is an interesting parallel to the chronic enterovirus infections of the stomach in ME/CFS. In both these chronic stomach and chronic liver infections, sickness behavior may be similarly induced, via IL-1β and the vagus.
What I don't get in a vagus infection theory is the weird timing of PEM although I admit that that is hard to explain whatever theory one has.
There are of course two aspects to the weird timing of PEM: the first aspect is the long duration of PEM, which can last for days, or even weeks. This timescale could be fairly easily explained by exercise-released IL-6, because as mentioned, IL-6 can stay at elevated levels in the blood for days or weeks after exercise.
What's a bit more difficult to explain is the second aspect, the timing of the arrival of PEM. In some patients PEM starts immediately after exercise, in others it starts hours later or the next day, and in some patients, PEM may only begin several days after exercise. How could this variable delay in arrival be explained by the IL-6 released from exercise?
That's certainly not easy to figure out. One might speculate, as you did, that there may be some muscle abnormalities in ME/CFS, which causes a delayed release of IL-6 in some patients. However, the following excerpt from
this paper suggests that there is no abnormal delay in the post-exercise release of IL-6 in ME/CFS:
Gupta, Aggarwal, and Starr (1999) reported that when CFS patients were tested twice, once when feeling a typical level of fatigue for their condition and once during a natural SF [Symptom Flare, ie, PEM], they showed significantly greater IL-6 levels during the SF.
They also attempted to experimentally induce SF through exercise, but only examined cytokine responses immediately after exercise, before the SF was manifested, when CFS patients and controls did not differ.
The caveat is that I am not sure how many patients were in that study.
So if it's not the muscles causing a delayed release in IL-6, then something else must be causing the delayed arrival of PEM.
There are a few factors that modulate the effects of IL-6 — factors that can switch IL-6 from being anti-inflammatory to pro-inflammatory — and perhaps these factors might be involved in creating the delayed start of PEM. Sickness behavior I believe is only precipitated when IL-6 works in its pro-inflammatory mode.
