Preprint A Peripheral Neuron-to-Microglia Signaling Axis Connecting Transient Viral Infection to Persistent Neuroinflammatory States Tenoever et al.

[Jaybee00]

Abstract​

Acute viral infections can cause lasting symptoms in anatomically distant, uninfected tissues, a phenomenon that challenges traditional notions of viral pathogenesis. A leading example is long COVID, a condition in which neurological and other clinical symptoms can materialize long after viral clearance1.

In investigating the mechanisms underlying this phenomenon, we found that despite evading direct infection, olfactory sensory neurons (OSNs) demonstrate a progressive slow decline following SARS-CoV-2 infection, triggering a prolonged neuroinflammatory response that persists for weeks to months post viral resolution.

Using both small animal models and human clinical samples, we demonstrate that the virus selectively infects sustentacular cells in the olfactory epithelium (OE), leading to structural disruption and secondary OSN loss. Axonal debris from degenerating OSNs accumulates in the olfactory bulb (OB), where it triggers sustained activation of resident microglia cells and persistent inflammatory signaling. These immune responses are spatially restricted to OB regions innervated by the damaged neurons and are marked by transcriptional programs involved in phagocytosis, synaptic remodeling, and debris clearance.

Together, these findings delineate a conserved neuron-to-glia injury axis in which peripheral neuronal damage initiates a protracted cascade that, despite the absence of direct central nervous system infection, culminates in delayed and persistent neuroinflammation. This mechanism offers a unifying framework for how transient respiratory infections can lead to persistent neurological sequelae, including those seen in long COVID.

A Peripheral Neuron-to-Microglia Signaling Axis Connecting Transient Viral Infection to Persistent Neuroinflammatory States

Acute viral infections can cause lasting symptoms in anatomically distant, uninfected tissues, a phenomenon that challenges traditional notions of viral pathogenesis. A leading example is long COVID, a condition in which neurological and other clinical symptoms can materialize long after viral...

www.researchsquare.com

 

[Jonathan Edwards]

This is potentially interesting but the last two abstract sentences are unhelpful.

Together, these findings delineate a conserved neuron-to-glia injury axis in which peripheral neuronal damage initiates a protracted cascade that, despite the absence of direct central nervous system infection, culminates in delayed and persistent neuroinflammation. This mechanism offers a unifying framework for how transient respiratory infections can lead to persistent neurological sequelae, including those seen in long COVID.

They would do better not to mention neuroinflammation. It ends with local gliosis, which seems of no great interest. And so it doesn't offer a unifying framework for anything much, certainly not for brain fog or fatigue or OI or whatever.

I wondered if active neural signalling (in intact peripheral nerves) might trigger glial activity of genuine relevance to LC symptoms, like "fatigue" - maybe in hypothalamus. It is another pathway we haven't really explored yet. But I am not sure why glia need to be involved. It could all be done by neurons. (Maybe glia would be good at mediating symptoms over a period of hours or a few days where neurons would be too off and on.)

 

[Utsikt]

Are they saying that the virus results in injury/death of certain neurons, and that these neurons are very long so the immune system takes a long time to clear them out?

Wouldn’t that be a process that eventually resolves?

 

[Jaybee00]

Bluesky thread

Bluesky

bsky.app

This is a potentially exciting new insight. It would be good to understand if this mechanism is limited to viruses infecting the olfactory epithelium (respiratory viruses such as influenza and SC2) with involvemnt and the decline of olfactory sensory neurons critical, and if
6/7

results can be extrapolated to ME/CFS. Therapeutic oppertunities may eventually be derived from this, although how to enhance clean up will be difficult. Reducing (neuro)inflammation (e.g. steriods) may be the target.

A manuscript to keep an eye on!

 

[Jonathan Edwards]

Are they saying that the virus results in injury/death of certain neurons, and that these neurons are very long so the immune system takes a long time to clear them out?

Wouldn’t that be a process that eventually resolves?

The nerves are relatively short - from nose to brain is only an inch or two. But it seems that they gradually die and their dead bodies in the brain need tidying away by glia. The 'immune system' isn't really involved as far as I can see, beyond local scavenger cells being in theory part of it.

I think the message is that it does resolve and without knock on effects on the rest of brain, but I have not read the full paper.

 

[Jonathan Edwards]

and if results can be extrapolated to ME/CFS.

It looks fairly clear that this is not going to be relevant to ME/CFS. Olfactory nerves are very peculiar and rather susceptible to damage in various situations such as drug therapies. We have no evidence for other nerves dying off in ME/CFS.

 

[poetinsf]

This might have a chance of explaining LC. But how would it apply to, say, mono? Or ME/CFS from non-viral causes? Maybe it is one of the ways of microglial activation. But probably not the only way.