A new study strengthens the view that SARS-CoV-2:
disrupts brain homeostasis,
alters ionic & neurotransmitter balance,
and triggers lasting epigenetic reprogramming.
Researchers exposed human primary astrocytes to Delta and Omicron.
The results are striking🧵
disrupts brain homeostasis,
alters ionic & neurotransmitter balance,
and triggers lasting epigenetic reprogramming.
Researchers exposed human primary astrocytes to Delta and Omicron.
The results are striking🧵
Astrocytes were infected with Delta and Omicron at a very low viral load (MOI 0.2).
After just 6 hours, RNA-seq revealed major transcriptional shifts
Omicron deregulated 346 genes (197 ↑, 149 ↓)
Delta deregulated 341 (215 ↑, 126 ↓)
About half of the changes overlapped.
Even minimal exposure triggered broad molecular changes within hours.
After just 6 hours, RNA-seq revealed major transcriptional shifts
Omicron deregulated 346 genes (197 ↑, 149 ↓)
Delta deregulated 341 (215 ↑, 126 ↓)
About half of the changes overlapped.
Even minimal exposure triggered broad molecular changes within hours.
Viral sensing and immune response.
Astrocytes primarily activated TLR2, but not RIG-I or NLRP3 - meaning they sensed the virus without launching a full antiviral storm.
Only 16 genes involved in interferon and interleukin signaling were affected.
Astrocytes primarily activated TLR2, but not RIG-I or NLRP3 - meaning they sensed the virus without launching a full antiviral storm.
Only 16 genes involved in interferon and interleukin signaling were affected.
This represents a low-grade immune activation, not an acute inflammation. It’s exactly the kind of chronic, silent neuroinflammation seen in long COVID.
Neurotransmitters - the brain’s language disrupted.
The infection rewired how astrocytes handle major neurotransmitters:
Glutamate
↓ EAAT1 (SLC1A3) & EAAT2 (SLC1A2) - impaired glutamate uptake - excitotoxicity risk.
↑ mGluR5 (GRM5) - linked to anxiety, depression, and suicidal behavior.
Too much glutamate = neuronal overactivation, sleep disruption, cognitive overload.
The infection rewired how astrocytes handle major neurotransmitters:
Glutamate
↓ EAAT1 (SLC1A3) & EAAT2 (SLC1A2) - impaired glutamate uptake - excitotoxicity risk.
↑ mGluR5 (GRM5) - linked to anxiety, depression, and suicidal behavior.
Too much glutamate = neuronal overactivation, sleep disruption, cognitive overload.
GABA
↓ GABRB2, ↑ GABRG3 - loss of inhibitory control.
The brain loses its brake.
Purinergic (ATP) signaling
↓ P2RY1, P2RY6, P2RY11; ↑ ENTPD2 - disrupted energy & sleep regulation.
The brain’s timekeeping and energy balance start to fall apart.
↓ GABRB2, ↑ GABRG3 - loss of inhibitory control.
The brain loses its brake.
Purinergic (ATP) signaling
↓ P2RY1, P2RY6, P2RY11; ↑ ENTPD2 - disrupted energy & sleep regulation.
The brain’s timekeeping and energy balance start to fall apart.
Neurotrophic factors - a protective overreaction.
Astrocytes increased BDNF, NT-4, GDNF, and TrkC (NTRK3) - an attempt to protect and remodel neurons.
But over time, this may lead to maladaptive rewiring rather than repair.
Meanwhile, NRTN (a motor neuron protector) dropped - reducing resilience.
Astrocytes increased BDNF, NT-4, GDNF, and TrkC (NTRK3) - an attempt to protect and remodel neurons.
But over time, this may lead to maladaptive rewiring rather than repair.
Meanwhile, NRTN (a motor neuron protector) dropped - reducing resilience.
The BBB - the vascular barrier also shifted.
↑ EDN1 (endothelin-1) - promotes vascular permeability.
Tight junction proteins changed unevenly - CLDN16 rose, but CLDN3, 7, 15 fell.
The BBB doesn’t simply open - it becomes patchy and unstable, allowing microscopic leaks and immune infiltration.
↑ EDN1 (endothelin-1) - promotes vascular permeability.
Tight junction proteins changed unevenly - CLDN16 rose, but CLDN3, 7, 15 fell.
The BBB doesn’t simply open - it becomes patchy and unstable, allowing microscopic leaks and immune infiltration.
Non-coding RNAs - the epigenetic fingerprint.
Astrocytes dramatically altered regulatory RNAs
↓ BDNF-AS - transient rise in BDNF, but disrupted long-term control.
↓ MALAT1 & NEAT1 (especially in Omicron sic) - loss of neuroprotective tone, weaker BBB integrity.
These are epigenetic changes - durable shifts in how the cell reads its genome.
They may underlie the persistent cognitive and neurological symptoms of long COVID.
Astrocytes dramatically altered regulatory RNAs
↓ BDNF-AS - transient rise in BDNF, but disrupted long-term control.
↓ MALAT1 & NEAT1 (especially in Omicron sic) - loss of neuroprotective tone, weaker BBB integrity.
These are epigenetic changes - durable shifts in how the cell reads its genome.
They may underlie the persistent cognitive and neurological symptoms of long COVID.
Delta vs Omicron - two paths, same destination
Delta acted more aggressively, with stronger cytokine signaling and deeper glutamate imbalance.
Omicron was quieter, but it rewired regulatory layers - especially noncoding RNAs like MALAT1 and NEAT1.
Delta acted more aggressively, with stronger cytokine signaling and deeper glutamate imbalance.
Omicron was quieter, but it rewired regulatory layers - especially noncoding RNAs like MALAT1 and NEAT1.
In short.
Delta burns fast (acute dysfunction),
Omicron programs slow (lasting dysregulation).
Both impair astrocyte health - and with it, the brain’s ability to keep itself in balance.
Delta burns fast (acute dysfunction),
Omicron programs slow (lasting dysregulation).
Both impair astrocyte health - and with it, the brain’s ability to keep itself in balance.
Sum:
SARS-CoV-2 reprograms the brain - quietly but deeply.
Disrupting homeostasis
Distorting neurotransmission
Rewriting epigenetic control
These are measurable, biological changes - not psychological aftereffects.
And they appear within hours of exposure.
SARS-CoV-2 reprograms the brain - quietly but deeply.
Disrupting homeostasis
Distorting neurotransmission
Rewriting epigenetic control
These are measurable, biological changes - not psychological aftereffects.
And they appear within hours of exposure.
Bhide et al., Comprehensive mapping of the signaling events evoked by SARS-CoV-2 variants Delta and Omicron in human astrocytes. nature.com/articles/s4159…
What emerges here are striking parallels to viruses known for long-term neuroimmune interference - HIV, EBV, CMV.
All manipulate host gene expression, silence antiviral responses, and reshape glial signaling to secure persistence within the nervous system.
All manipulate host gene expression, silence antiviral responses, and reshape glial signaling to secure persistence within the nervous system.
SARS-CoV-2 now shows the same pattern:
low-grade inflammation, altered cytokine balance, disruption of neurotransmitter circuits, and epigenetic reprogramming of astrocytes.
low-grade inflammation, altered cytokine balance, disruption of neurotransmitter circuits, and epigenetic reprogramming of astrocytes.
The difference is scale and timing -
what those viruses evolved over millennia to sustain chronically, SARS-CoV-2 is already beginning to reproduce through its post-acute effects.
what those viruses evolved over millennia to sustain chronically, SARS-CoV-2 is already beginning to reproduce through its post-acute effects.
It doesn’t just set the stage for chronicity.
It’s demonstrating it, biologically and clinically.
It’s demonstrating it, biologically and clinically.
It doesn’t merely trigger inflammation.
It shows a long-term shift toward neuroimmune exhaustion.
It shows a long-term shift toward neuroimmune exhaustion.
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