A new preprint study shows that the SARS-CoV-2 protein ORF6 directly kills human neurons.
Not by accident, but through necroptosis - a kind of cell death where neurons burst and fuel inflammation.
This may underlie the long-term brain symptoms of Long COVID.🧵
Not by accident, but through necroptosis - a kind of cell death where neurons burst and fuel inflammation.
This may underlie the long-term brain symptoms of Long COVID.🧵
https://twitter.com/atranscendedman/status/1965077088798662767
Researchers tested 22 viral proteins. The most toxic? ORF6.
In neurons, it flipped on the necroptosis switch - RIPK3 and MLKL.
Biologically - these molecules punch holes in the cell membrane until the neuron literally ruptures.
In neurons, it flipped on the necroptosis switch - RIPK3 and MLKL.
Biologically - these molecules punch holes in the cell membrane until the neuron literally ruptures.
In patient brain tissue, especially the hippocampus (memory center), they found the same pattern
dead neurons + necroptosis markers.
That’s a direct biological link between infection and symptoms like brain fog and memory loss.
dead neurons + necroptosis markers.
That’s a direct biological link between infection and symptoms like brain fog and memory loss.
How? ORF6 binds to a mitochondrial protein called MTCH1.
Mitochondria then
lose their charge (membrane potential)
overload with calcium
spew toxic oxygen radicals
All signals that trigger neuronal death.
Mitochondria then
lose their charge (membrane potential)
overload with calcium
spew toxic oxygen radicals
All signals that trigger neuronal death.
When MTCH1 was silenced or RIPK3 was blocked, neurons survived.
So the pathway is clear: ORF6 - MTCH1 - mitochondrial chaos - necroptosis.
That’s not collateral damage! It’s a defined, druggable mechanism.
So the pathway is clear: ORF6 - MTCH1 - mitochondrial chaos - necroptosis.
That’s not collateral damage! It’s a defined, druggable mechanism.
Out of this study.
Other research shows ORF6 has more tricks.
It binds the Nup98–Rae1 complex and blocks key defense proteins (STAT1/2, IRF1, NLRC5) from entering the nucleus.
That means cells can’t turn on antiviral genes or display viral pieces on their surface for T cells to see.
Other research shows ORF6 has more tricks.
It binds the Nup98–Rae1 complex and blocks key defense proteins (STAT1/2, IRF1, NLRC5) from entering the nucleus.
That means cells can’t turn on antiviral genes or display viral pieces on their surface for T cells to see.
The result:
Interferon signaling - the body’s rapid antiviral alarm - is shut off.
MHC-I presentation - the billboard that tells CD8 T cells which cells are infected - is blocked.
This is the same strategy HIV uses via its Nef protein to persist in the body!
Interferon signaling - the body’s rapid antiviral alarm - is shut off.
MHC-I presentation - the billboard that tells CD8 T cells which cells are infected - is blocked.
This is the same strategy HIV uses via its Nef protein to persist in the body!
ORF6 also breaks genome integrity.
It degrades CHK1, a checkpoint enzyme that safeguards DNA replication.
Without CHK1, cells run out of DNA building blocks, stall, accumulate DNA breaks, and age prematurely.
It degrades CHK1, a checkpoint enzyme that safeguards DNA replication.
Without CHK1, cells run out of DNA building blocks, stall, accumulate DNA breaks, and age prematurely.
It also drives R-loops - tangled RNA–DNA hybrids that jam replication forks.
The result - more replication stress, genome instability, and inflammatory signals.
The result - more replication stress, genome instability, and inflammatory signals.
So ORF6 damages the brain in two ways:
Directly - killing neurons through mitochondrial necroptosis, damaging DNA.
Indirectly - sabotaging immunity, allowing viral persistence and chronic inflammation
Directly - killing neurons through mitochondrial necroptosis, damaging DNA.
Indirectly - sabotaging immunity, allowing viral persistence and chronic inflammation
Reviews of Long COVID point to the same culprits in cognitive dysfunction.
Chronic neuroinflammation
Leaky blood–brain barrier
Endothelial dysfunction and microclots
Immune evasion
ORF6 ties into all of them.
Chronic neuroinflammation
Leaky blood–brain barrier
Endothelial dysfunction and microclots
Immune evasion
ORF6 ties into all of them.
ORF6 is one of the most dangerous SARS-CoV-2 proteins.
Not just an accessory - but a neurotoxin, a genotoxin, and an immune saboteur in one.
Ignoring it means ignoring viral persistence and the risk of long-term cognitive harm.
Not just an accessory - but a neurotoxin, a genotoxin, and an immune saboteur in one.
Ignoring it means ignoring viral persistence and the risk of long-term cognitive harm.
This is a preprint and based on a small autopsy series (5 COVID-19 brains).
But despite the limited sample, the findings fit neatly with what we already know about ORF6 - immune evasion, DNA damage, and now direct neuronal toxicity.
But despite the limited sample, the findings fit neatly with what we already know about ORF6 - immune evasion, DNA damage, and now direct neuronal toxicity.
Seth at al., SARS-CoV-2 Orf6 Triggers MTCH1-Dependent Mitochondrial Dysfunction and Necroptosis in Human Neurons. researchsquare.com/article/rs-729…
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