T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses, 2019, Garber+

[forestglip]

T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from neuropathogenic flaviviruses

Spoiler: Authors

Garber, Charise; Soung, Allison; Vollmer, Lauren L.; Kanmogne, Marlene; Last, Aisling; Brown, Jasmine; Klein, Robyn S.

Published: 2019

[Line breaks added]

Abstract
T cells clear virus from the CNS and dynamically regulate brain functions, including spatial learning, through cytokine signaling. Here we determined whether hippocampal T cells that persist after recovery from infection with West Nile virus (WNV) or Zika virus (ZIKV) impact hippocampal-dependent learning and memory.

Using newly established models of viral encephalitis recovery in adult animals, we show that in mice that have recovered from WNV or ZIKV infection, T cell-derived interferon-γ (IFN-γ) signaling in microglia underlies spatial-learning defects via virus-target-specific mechanisms.

Following recovery from WNV infection, mice showed presynaptic termini elimination with lack of repair, while for ZIKV, mice showed extensive neuronal apoptosis with loss of postsynaptic termini.

Accordingly, animals deficient in CD8+ T cells or IFN-γ signaling in microglia demonstrated protection against synapse elimination following WNV infection and decreased neuronal apoptosis with synapse recovery following ZIKV infection.

Thus, T cell signaling to microglia drives post-infectious cognitive sequelae that are associated with emerging neurotropic flaviviruses.

Web | Nature Neuroscience | Paywall

 

[forestglip]

This abstract appears to say that IFN-gamma signalling to microglia causes post-acute symptoms in mice after a couple different viral infections. One of the effects was damage to synapses.

 

[Jonathan Edwards]

It is hard to know whether one can extrapolate usefully from neurotropic viruses. I don't to what extent these two are neurotropic in mice.

 

[forestglip]

Still, maybe it shows that synapse damage is why brain IFN-g and microglia activation are associated with post-acute symptoms in this other study that used a coronavirus: Neuropsychiatric sequelae in an experimental model of post-COVID syndrome in mice, 2025, Pimenta et al

It might fit with genetic findings - synapses that function poorly, whether through genetic mutations or through damage caused by an infection, might increase risk of ME/CFS-like syndromes.

From discussion of that other paper:

Glutamate and Calcium

MHV-A59-infected female mice also had significant glutamate release and increased intracellular Ca2+ levels in the hippocampus at 30-dpi. This is suggestive of neuronal excitotoxicity, as viral infections, including HIV, ZIKA and H1N1, have already been shown to impair glutamatergic transmission, thus impairing neural signaling (Costa et al., 2017; Düsedau et al., 2021; Gorska and Eugenin, 2020).

Microglia

Importantly, a greater number of microglia/macrophage (IBA-1) and astrocytes (S100B) were found in the cerebral cortex and hippocampus of female mice when compared to male mice. The increased number of these cells is suggestive of enhanced neuroinflammation and possibly neurodegeneration (Kwon and Koh, 2020; Vandenbark et al., 2021).

Nitric oxide synthase

Moreover, microglia of infected female mice but not male mice showed high expression of inducible nitric oxide synthase (iNOS). Nitric oxide (NO) is essential in synaptic transmission and brain plasticity, mainly in the cortex and hippocampus. However, high levels of NO and nitrergic/ oxidative stress can lead to synaptic impairment and early neuro degeneration (Balez and Ooi, 2016).

IFN-G releasing CD4+ T cells

The more robust neuroinflammation in female mice was further confirmed by detection of immune cells in the brain. MHV-A59-infected female mice presented increased number of IFN-γ+-releasing CD4+ T lymphocytes in the brain, with Ki67+ (cell proliferation marker) and CD69 (cell activation marker) expression, aside higher numbers of Ki67+ CD8+ T cells in relation to males.

T cells are especially important for limiting viral replication, as they can gain access to brain parenchyma through local recognition of viral antigens by T cell receptors (Steinbach et al., 2016). The interaction between microglia and T cells is also crucial within the CNS parenchyma, since the effector functions of these lymphocytes depend on this communication (Ai and Klein, 2020). However, when this response is not finely regulated, the results can be deleterious.

A study demonstrated that T cells might be associated with neurocognitive sequelae in surviving animals during neuropathogenic viral infections, such as ZIKV and West Nile Virus (WNV). This occurs mainly through the signaling of IFN-γ released by specific CD8+ T cells infiltrating the CNS, which induces the activation of microglia (Garber et al., 2019 [this thread's study]). This microglial activation is correlated with several neurotoxic effects, such as excessive complement-mediated synapse elimination, neurodegeneration and decreased adult neurogenesis (Klein et al., 2019).

WT mice infected with MHV V5A13.1 presented CNS inflammation and demyelination significantly less severe than T CD4− /− mice (Lane et al., 2000).

 

[Creekside]

Does this synapse damage theory fit the observed effects? Would that theory cause effects that aren't observed (loss of specific memories, for example)?

 

[forestglip]

Does this synapse damage theory fit the observed effects? Would that theory cause effects that aren't observed (loss of specific memories, for example)?

I don't know any specific ways that weak synapses can lead to symptoms. But synapses are involved in every function of the nervous system, so I imagine pretty much any brain-associated symptoms are theoretically possible.

Synapse involvement was discussed on this thread: https://www.s4me.info/threads/the-s...s-involving-neurons-and-their-synapses.45734/

 

[hotblack]

Interesting. I’ve been wondering about astrocytes and their general housekeeping at the synapse but this seems a bit clearer on a potential mechanism and shared upstream trigger for different virus induced problems.

The full paper and PDF is available on Pubmed Central btw
PMC | PDF

 

[hotblack]

CX3CR1 has been talked about in various threads and contexts before on the forums. I particularly wonder about the relevance of this

On other papers I’ve commented on the use of CX3CR1 Cre mouse models, because CX3CR1 is expressed in many different contexts and may confound results by knocking out the gene in an unintended cell type

The paper mentions this in the discussion too

We therefore designed this experiment to limit the possibility that non-microglial myeloid cells were participating in the process. Nevertheless, as CXC3R1 is not a specific microglial marker, non-microglial cells could possibly contribute to the results obtained.

 

[hotblack]

Most of the methods are beyond me, would be good to get more insight from some experts, but if I’m understanding the paper correctly they’re saying (and sorry if this is repeating, just helps me work out what is being said!)

• Two different viruses, with two different routes (presynaptic elimination in one and neuronal death and loss of post-synaptic termini in the other) to a similar cognitive impact post infection.
• A proposed shared pathway of T-cells producing IFN gamma which causes microglial activation.
• Tested by using mice without the IFN gamma receptor or without CD8+ T cells.
• These mice didn’t show the same cognitive impact.
• Deletion of the IFN gamma receptor after viral clearance was enough to prevent the cognitive impacts, indicating this is a post infectious pathway.
• Interleukin-1 beta only shows up in one of the virus pathways.

 

[Jonathan Edwards]

To me these are just standard pathways that are likely to be involved in brain damage. If you cut any one pathway you tend to see an improvement in an animal model set up to be bad enough to measure but not so bad nothing can alter it.

T cells will activate microglia, yes. In brain that is likely to knock synapses. I don't it as very likely that this is relevant to ME/CFS where we do not see severe memory loss as in head injury for instance.

 

[Creekside]

I don't it as very likely that this is relevant to ME/CFS where we do not see severe memory loss as in head injury for instance.

That's what I meant with my previous question. Would this theory result in something we don't see, such as PWME unable to remember the letter W, or number 8 or whatever random synapse loss might cause? Is there enough redundancy that losing synapses at a rate proposed in this theory wouldn't show significant symptoms of that type ... yet cause the typical ME symptoms?

 

[forestglip]

My thinking was that it would depend which synapses and how severe the damage is. For example, maybe in ME/CFS the damage is away from memory-associated neurons and mild enough to not be visible on scans, but enough damage to throw off a delicate system, like maybe the sickness response pathways.

 

[hotblack]

It was the potential pathway I suppose I found interesting in here. But if it’s nothing new/unexpected as @Jonathan Edwards says I’m not sure what to make of it.

The idea of recoverable impacts on synapses from a shared pathway upstream of viruses seemed to tick a lot of boxes. If this process could be triggered by some immune activity other than a virus (like in some other ideas about the intersection of mitochondria, cGAS-STING and innate immunity) even better. At least for someone like me in the more vague hand wavey realm.

And like @forestglip says seemed to conceptually fit in with the “what makes people feel rubbish after being ill” discussions. So thanks for sharing the paper

 

[Jonathan Edwards]

Is there enough redundancy that losing synapses at a rate proposed in this theory wouldn't show significant symptoms of that type ... yet cause the typical ME symptoms?

I think one can take concussion or ECT as examples where we have reason to think synapses get broken up. You get amnesia and lose memory for past events and you can also get loss of procedural memory. That means you get a fork out to beat an egg and your arm doesn't remember how to do it without sloshing the egg everywhere (roughly what happened with my wife - all 3). I don't hear of people with ME/CFS suffering these things. I hear of it being difficult to do mental tasks quickly or to do complicated mental tasks at all but I don't hear of not remembering that your uncle died recently or how to put your socks on.

 

[Creekside]

And like @forestglip says seemed to conceptually fit in with the “what makes people feel rubbish after being ill” discussions.

Well, there are so many other possibilities, that "just sort of fitting in if you don't look too closely" doesn't mean much. I'd put "excess quinolinic acid from brain cells" much higher for "feeling rubbish".

 

[hotblack]

Well, there are so many other possibilities, that "just sort of fitting in if you don't look too closely" doesn't mean much. I'd put "excess quinolinic acid from brain cells" much higher for "feeling rubbish".

I’d say both mean as much or as little as each other until we have evidence no harm in exploring and discussing new ideas, it’s how we discover things after all isn’t it?

 

[Creekside]

no harm in exploring and discussing new ideas

Well, there is harm in allocating limited resources to a theory that is lacking in evidence compared to others. At this point there isn't much evidence for any of them, although there is counterevidence (things not found from testing, such as obvious viral infections).

This makes me wonder: are some research specialties better at getting funding? For example, are studies about viral causes more likely to get funding from Big Pharma, since it could lead to a profitable product? Studies about glial cells might be less likely to directly result in profitable products.

 

[Kitty]

I hear of it being difficult to do mental tasks quickly or to do complicated mental tasks at all but I don't hear of not remembering that your uncle died recently or how to put your socks on.

You don't seem to get strange things like postural effects either.

I was rested and sharp enough last night to play music and join in the craic, but after walking the eight feet to bar I'd lost the word 'soda'. I had to ask for water with fizz in it—then add I didn't want any 'stuff', in the hope the fella would realise that meant ice and lemon.

Sat down again, and reverted to being the only one who could recall the names of the string of tunes we'd just played so the new guy could note them down.

It's very odd.

 

[Creekside]

https://newatlas.com/sleep/brain-focus-lack-of-sleep/

"So MIT scientists peeked inside sleep-deprived brains and found something surprising: the brain tries to clean itself even when you're awake. Usually, this "cleaning" occurs during deep sleep, when waves of cerebrospinal fluid (CSF) flush waste products from the brain. But when you're running on little sleep, those waves sneak into your waking hours, right when your attention falters."

@Kitty Maybe the walk to the bar put you in that cleaning cycle.

 

[Kitty]

Maybe the walk to the bar put you in that cleaning cycle.

It would certainly explain a lot if they only happen when I stand up, given that I can't sustain it for more than a couple of minutes! My brain feels like an explosion in a sock factory—unravelled wool everywhere.