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/