An airway-to-brain sensory pathway mediates influenza-induced sickness 2023 Bin et al

[rvallee]

How the brain senses a flu infection — and orders the body to rest

"A case of influenza can make even the toughest people take to their beds and lose their appetites. Now, scientists have identified neurons in mice that notify the brain of a flu infection, triggering decreases in movement, hunger and thirst1.

Similar neurons connecting to other parts of the body might notify the brain of other infections, too, the authors say. The work was published on 8 March in Nature.

“This study flips previous thinking on its head,” says Ishmail Abdus-Saboor, a sensory biologist at Columbia University in New York City who was not involved in the research. “This is paradigm-shifting in terms of how we think about sickness behaviour.”"

https://www.nature.com/articles/d41586-023-00675-0

I'm reading around this part of the article and I don't understand what is paradigm-shifting here? This is sickness behavior, what is different about this other than that they didn't know about specific neurons being involved, and possibly which molecules act on it?

If you'd have put this description to me, I would have thought this is already the paradigm, other maybe than knowing exactly the where and how. What is the current paradigm if not that? The psychosocial stuff?

 

[rvallee]

I am seriously baffled at the discussion over the evolutionary aspect of the sickness response and the "paradox" that it's better to alleviate it.

Because this is exactly what's expected. It has an evolutionary advantage in nature, not in a controlled lab. This is exactly what is expected. This response is not to promote the organism's survival in an artificial setting, an evolutionary response acts as a pressure in a natural environment on a scale of generations.

Again just the weird expression of puzzlement at finding exactly what's expected is just alarming. Being ill in nature is a good way to get eaten. Being ill in a cage in a lab isn't. No paradox here.

 

[Hutan]

I'm reading around this part of the article and I don't understand what is paradigm-shifting here? This is sickness behavior, what is different about this other than that they didn't know about specific neurons being involved, and possibly which molecules act on it?

The authors showed that a specific prostaglandin receptor, called EP3, is responsible for generating sickness behaviours. EP3 is found on neurons throughout the body, including the brain. To test its function, the researchers deleted the brain’s EP3 receptors in mice and infected the animals with flu virus. The mice still changed their behaviour — indicating that the brain is not getting infection dispatches from blood-borne prostaglandins.

I think you are right @rvallee. The finding is just about the specific tissue involved, in mice, responding to the flu. I think it probably isn't paradigm changing, yet at least.

It just tells us a lot more about how the sickness response happens and raises more questions, better questions.

The body makes prostaglandins at the site of an infection or tissue damage, and those prostaglandins, acting on prostaglandin receptors in that local tissue can produce a system-wide response that includes changes in behaviours, such as reduced activity. It seems likely that the prostaglandins produce some of their effects directly. For example, some prostaglandins can cause vasodilation, some can cause vasoconstriction, some can activate clot formation, which is handy if there is a cut. But, I don't think we can rule out that the local tissue is mostly just sending a message to the brain via the neurons, and then the brain governs much of the sickness response as has always been thought.

The reduced sickness response when the particular neurons were cut could mean that a message has to get to the brain to produce a sickness response in the round. But of course, if the neurons with the prostaglandin receptors are dead, then they can't be acting locally either. It makes sense that there are both local and central responses.

 

[SNT Gatchaman]

Of course, 'sickness behaviour' is a non-BPS term meaning the types of behaviours and signs that animals exhibit when sick - withdrawing from others, reducing activity, reducing food intake, fever (with pain and fatigue, for example, used to produce the behavioural response).

We have seen the phenomenon instead labelled 'sickness response', which is perhaps better, as it avoids confusion with malingering.

Or maybe "sickness programme"?

 

[Ravn]

What do you think about the ME/CFS=chronic sickness response theory?

Haven't read the paper but what's most interesting to me is that - assuming I picked this up correctly from the snippets here - is

1) that the sickness response may be made up of several parts which function independently of each other to some degree, and

2) that the sickness response may originate in the periphery.

Point 1 is interesting because to me it doesn't look like our ME symptoms quite match the typical sickness response which includes fever and lack of thirst for example. Some pwME undoubtedly experience those but many don't, and some experience the opposite, too low a body temperature and increased thirst during PEM. So to me the typical sickness response and the ME symptom picture look similar but not quite the same. But could it be that in ME only some selected parts of the standard sickness response are activated (together with plenty of other stuff going wrong at the same time)? Or even that a failure to activate the entire sickness response at the appropriate time is the problem?

Point 2 is interesting because it points to the possibility of a primary problem in the periphery, not in the brain. Only a possibility though, there's bound to be some primary brain mechanism(s) which can trigger a sickness response, too

 

[JemPD]

Point 1 is interesting because to me it doesn't look like our ME symptoms quite match the typical sickness response which includes fever and lack of thirst for example. Some pwME undoubtedly experience those but many don't, and some experience the opposite, too low a body temperature and increased thirst during PEM.

yes my temp tends to drop to low end of normal 36 ish when in PEM with increased thirst, but i also get increased thirst during viral infections, its always been marked that when i am ill i get very thirsty, regardless of the infection. And i rarely lose my appetite unless i have a sickness/diarrhoea bug or a migraine - with flu etc i can still eat its just that what i want changes & obviously its difficult with a sore throat if it hurts too much to swallow.

I'm just wondering if this discovery in mice might be useful in further investigating any kind of signalling problem in ME @Jonathan Edwards

 

[Hutan]

2) that the sickness response may originate in the periphery.

As Rvallee noted, a sickness response pretty much always had to, and has to originate in the periphery, because that is where the infections start. And it makes sense that at least some of the sickness response happens locally, without the brain getting involved e.g. responses to tissue damage.

too low a body temperature

I've seen low body temperature also referred to as a possible sickness response symptom. e.g. here:

When you have an infection, your body's temperature usually rises as it tries to fight off the bug causing the infection. Interestingly, some people see their body temperature go down (hypothermia) instead of up. This is why any change, high or low, can be a sign of sepsis.

and here:

Thermoregulatory accompaniments of sickness behavior could be either fever or hypothermia depending on the nature and severity of disease. A survey of the relevant literature has identified afferent, central and efferent mechanisms that may allow separate or coordinated appearance of behavioral and/or thermoregulatory aspects of these symptoms occurring under different experimental conditions. An attempt has been made to find some biological logic in the appearance of various components of sickness behavior and changes in body temperature that could explain the purported positive value of sickness behavior in disease survival.

Sepsis in humans may indeed be by characterized either by fever or hypothermia (80) and in rats injected with high doses of LPS hypothermia may be observed either shortly after LPS challenge (81) or at the later phase of experimental sickness syndrome (10). The latter report gives evidence for a continuum of changes in body temperature starting with a hypermetabolic state with fever and pain under any thermal conditions which is than followed by a gradual reversal into a more passive, hypometabolic state, the latter allowing hypo- or hyperthermia depending on the thermal conditions of the environment. In other words, this later phase of „fever” may be characterized by a broad-band control of thermoregulation (82) with other components of sickness behavior (inactivity, anorexia, sleepiness, etc.) remaining largely the same.

A more or less marked lability of thermoregulation may be accounted for by an inability to increased heat production on cold exposure, widening of the so-called interthreshold zone of regulation (i. e. between core temperature threshold for increased heat loss and that for shivering). Interpretation of a fall in body temperature during severe illness ranges from an inability of central or peripheral thermoregulatory mechanisms to insure homeothermy, on the one hand, to a coordinated set of physiological changes leading to a lower set-point, hence to a „central” or regulated hypothermia. The latter interpretation envisages some purpose or biological logic that may serve survival of the sick individual. This opinion has been supported by the finding that rodents made hypothermic by hypoxia or various toxins may prefer lower ambient temperatures when the choice is given to them to seek an optimal thermal environment (83, 84, 85). As for the likely mechanism of hypothermia in animals injected with LPS the only study published so far indicates also a parallel change of selected ambient temperature and core temperature (81). Possible relationship between LPS- induced hypothermia and sickness behavior has not been studied in detail with one exception. In particular, body temperature, activity, food- and water-intake were followed in rats after an i.p. injection of high dose of LPS (86). A pretreatment with a TNF-binding protein led to an enhancement of LPS-fever, while the decrease in food- and water-intake was abolished. Interestingly, the initial hypothermia - indicating a shock-like state - and the fall in general activity remained unchanged after the inhibition of TNF-effect. These data support the notion that TNF may be regarded as a cryogenic mediator and demonstrate that various components of sickness behavior and the two phases of body temperature change (hyper- or hypothermia) may have partly different mediation, the nature of which are far from being clear.

Central or regulated hypothermia – sometimes called also anapyrexia when the phenomenon is supposed to act as an antipyretic mechanism – was observed under conditions which may also be present during disease states. Among others, hypoxia could be a pathophysiological state that may also accompany some diseases affecting circulation, respiration or metabolism. In fact, hypoxia induces hypothermia together with a decreased motor activity in rats and may disturb circadian changes of these two parameters differently (87). As for the mechanism of hypoxic hypothermia several mediators have been suggested such as nitric oxide (88) but not vasopressin (89), lactate known to be connected to tissue hypoxia acting as a metabolic inhibitor doses apparently not mediating this anapyrexic response, either (90). Another factor likely contributing to metabolic derangements in various disease states is hypoglycemia (91). According to recent studies the hem-oxigenase product, carbon monoxide may have a role in hypothermia of hypoglycemia induced by insulin in rats (92). The lack of information on changes in other aspects of sickness behavior does not allow any conclusions to be made on possible causal relationship between regulated hypothermia and symptoms of diseases affecting energy regulation.

 

[Sean]

I could understand that we might feel a bit better in the short term by eliminating a sickness response, but I suspect it would just at best result in delaying significant PEM rather than prevent it.

Exactly.

For example, if the itaconate shunt is switched on, there is a something like an inefficient system of producing energy, that produces waste products. There are lots of immune changes that could have downstream effects.

I would not be surprised if there is a whole cascade of stuff from whatever the primary pathology turns out to be.

 

[Jonathan Edwards]

I'm just wondering if this discovery in mice might be useful in further investigating any kind of signalling problem in ME @Jonathan Edwards

I suspect not in that the signalling they describe is well known. They have identified some specific airway nerves but that does not seem very relevant to ME.

I think that the study may serve to remind us that symptoms of feeling ill involve both peripheral and central signal components.

With flu, or for me in the post Covid weeks, it seems obvious that something is wrong with one's muscles or gut or nerves or joints etc. because they hurt or give other symptoms. But it is unlikely that there is anything wrong with the ability of these tissues to do their jobs other than being inhibited by danger signals.

It makes sense that these danger signals are coming all the way from the arms and legs or gut. But it is also useful to remember that the brain normally suppresses all sorts of signals from the body and that all we may need to get danger signals from the body is for the brain to turn the 'squelch button' The squelch button is what you had on VHF radios which is there to damp down signals until you can only hear the useful ones from other radios. If you turn squelch up you get lots of noise all the time.

These mechanisms are to some extent what people talk about in terms of peripheral and central sensitisation but that term has been highjacked by people who have special theories about how it works.

 

[Mij]

So to me the typical sickness response and the ME symptom picture look similar but not quite the same.

I got Covid or influenza last December. Symptoms involved sore throat, coughing, loss of appetite, no fever for 5 days. I experienced on and off leg muscle fatigue for a little over a week. I went back to baseline 3 weeks later and thought I had recovered, but when I went for my usual 50 minute brisk walk, I got up the next morning and couldn't stand on my legs for 3 weeks from severe leg muscle exhaustion. I had to eat canned food.

My M.E PEM is a completely different experience. It involves whole body fatigue (arms and legs), dehydration, shakiness, ataxia, slurred speech, cognitive impairment and chest pressure. I had none of that with sickness behaviour.

 

[JemPD]

shakiness, ataxia, slurred speech, cognitive impairment

yes i get all those too, but they come on top of sickness behaviour, so its like SB Plus. I would never call the weakness from sickness behaviour sensation 'whole body fatigue' - whole body fatigue is a qualitatively different experience for me.

I'm not trying to say it's about severity - a milder sickness behaviour experience can be much less disabling than PEM, or indeed than severe overwhelming exhaustion, its just a different bodily sensation for me. Which is, for me, unique to having an infection of some kind. So SB experience is identical to ME/PEM, plus the other symptoms added in on top. Although to be fair, when i have had bad doses of flu befor i have experienced some cognitive dysfunction

 

[Mij]

@JemPD

By SB, which is an adaptive response, are you saying that you feel as though you're fighting an infection during PEM?

My delayed PEM starts when I've gone over my energy limit. It's worse if I'm dealing with an infection of course, but it's tricky to fully know whether my immune system has cleared the virus from what I experienced recently.

 

[JemPD]

By SB, which is an adaptive response, are you saying that you feel as though you're fighting an infection during PEM?

oh yes absolutely.

As i said in my earlier post, (in response to Hutan's question what people thought about ME/CFS= chronic sickness response theory) the experience is identical - which i guess isnt strictly accurate really since i also have the other symptoms we talked about. Its identical & then some other bits on top.

One of the reasons that i get so upset by the 'fatigue' word is that i dont feel tired, even to the extremem of exhaustion, i feel ill. The experience is identical to flu/infection for me, to the point that it takes me a few days of non-fluctuating sore throat flu symptoms (chills aches nausea weakness dizziness) to realise i might have an actual fever & an infection, on the rare occasions i have caught something over the last 20yrs - i've never noticed it at the beginning just assuming its part of my ME, its only when there is no variation through the day & the sore throat is severe or cough unrelenting that raises my suspicions enough to reach for the thermometer.

And while extreme fatigue is debilitating when i have experienced it in the past, its just a qualitatively different bodily experience to having an infection of some kind. Its apples & oranges. So it has always felt as if my body was somehow mistaking exertion for infection

 

[V.R.T.]

thats one of the reasons why i dont take ibuprofen very often - it helps - which is a problem if you operate symptom contingent pacing.

When mild I essentially dosed up on ibuprofen daily for years, which masked the severity of my symptoms and led me to write the illness off as just repeated colds/infections

 

[Sean]

But it is also useful to remember that the brain normally suppresses all sorts of signals from the body and that all we may need to get danger signals from the body is for the brain to turn the 'squelch button'. The squelch button is what you had on VHF radios which is there to damp down signals until you can only hear the useful ones from other radios. If you turn squelch up you get lots of noise all the time.

Technically a (variable threshold) noise gate.

It is a potentially useful analogy, I think. If so, then the question is whether the noise gate mechanism itself is defective, or is it working properly but the signal it has to deal with has become too strong and/or distorted, and is now outside the normal operating parameters of the otherwise healthy noise gate?

Might be more than one noise gate mechanism in play too.

Interestingly, noise gates – at least in electronics – are not a simple on/off switch, they have other variable parameters like attack, hold, and release, and sometimes independent threshold levels for on and off, which may be relevant to understanding biological forms of noise gate.

https://en.wikipedia.org/wiki/Noise_gate