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A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in

So there's a ton of studies out there involving bacterial LPS, as this is the outer coat of bacteria that your immune system first recognizes as the sign of a bacterial infection. Inject it into mice and you get the symptoms of a bacterial infection (up to and including death at higher doses) without the actual infection. This tool helps researchers separate out the two factors. We now know, for example, when you have a sinus infection, the resulting pain, fatigue, bleariness, etc are primarily your body conning you into taking it easy so you don't use up the resources it needs to fight the infection. Very little of it has to do with the damage the bacteria are doing to your cells or any substances they secrete. However, subjectively, the result is very similar.

That means that if you do anything different than your daily routine such as not going for your normal 5k run after work, or microwaving some Campbell's soup instead of preparing a balanced meal, or calling into work sick and staying in your pajama pants all day, you're engaging in "sickness behaviour". You could just ignore all those symptoms and go about your normal day. Not that it would be a good idea. Your doctor would tell you not to, as you'd be encouraging the infection to spread into your throat and lungs, actually making it harder to breathe and potentially reducing your O2 sats, increasing "sickness". Subjectively, it would also feel terrible.

Now there is a useful underlying idea in this paper. It starts from several premises:
1) A number of mental illnesses are now known to have altered cytokine profiles from healthy controls.
2) Disease state does not necessarily correlate with concentration of cytokine "X".
3) "Sickness behaviour" lasts longer than would be expected, suggesting some sort of memory of infection.

So, these folks went and took normal, outbred mice and gave them LPS once systemically. The outbreeding is important because this means no specific phenotype present, and the population of mice tested should have some variability in response due to differences in genetics. These aren't ME or CFS mice. We don't know how to make those. Nor are they abnormally depressed mice. This, then, is the natural response to an immune challenge.

As a result of the LPS injection, the amount of TNF mRNA and serotonin receptor mRNA goes up. This means cells are potentially producing more TNF, and more receptors for serotonin.

Since no more LPS is injected (which is similar to eradication of a bacterial infection), the mice are expected to go back to normal after 24h.

They don't.

Therefore the body has modified itself, potentially by making cells more sensitive to serotonin and TNF.

This is conceptually similar to the paradigm of stem and progenitor cells, which have increased expression of growth factor receptors, causing them to replicate and differentiate better than other cells due to small changes in their environment.

My critiques:

1) The behavioural stuff is all a "hand waving argument", as one of my physics profs used to say. Since you can't ask the mice why they're doing what they're doing, there's no way to eliminate observer bias. Were they less active because they were tired, or sleepy? Did LPS make them less anxious, or break a lifetime ambition of burying as many marbles as possible?

2) The protein biochemist in me asks where the quantitative mass spec data proving there's more receptors being produced. Heck, I'd settle for a reasonable Western Blot.

However this actually could very nicely fold into the discovery that PWCFS for less than 3 years have different cytokine profiles than longer term patients. Maybe our bodies have shifted to a new normal, more sensitive to the aftereffects of exercise, resulting in PEM. Now how can we characterize that, at a cellular level?


Senior Member
What I found interesting in this study : post infectious kynurenine increases in gut and plasma but decreases in cortex and even lower in hippocampus