Thread by @ZdenekVrozina

SARS-CoV-2 can turn our own defenders into traitors.
A study in Sci Transl Med, 2025 shows the virus drives neutrophils into PMN-MDSCs cells that don’t fight, but suppress T cells.🧵

https://twitter.com/alberto_roman83/status/1968722604425900342

Instead of attacking the virus, these neutrophils hit the brakes on adaptive immunity.
T cells divide less, signal less.
The immune response collapses from within - right when it should be gaining strength.

And this is not just correlation.
Simply exposing neutrophils to SARS-CoV-2 in vitro was enough to reprogram them.
Contact with viral particles or proteins alone triggered the shift into PMN-MDSCs.
The virus can actively manipulate immunity from the start - not just passively ride the inflammation.

How? Likely through TLRs Toll-like receptors.
SARS-CoV-2 proteins activate TLR2/4, viral RNA hits TLR7/8 - leading to degranulation and dysfunctional neutrophil programming.
This TLR–MDSC axis is well known in cancer - the virus just weaponizes it acutely.

And there’s another layer - the microbiota.
Gut bacteria constantly tune TLR sensitivity. Probiotics and microbial metabolites can modulate TLR2/4 and dampen runaway inflammation.
Not a magic bullet for COVID - but a reminder that our gut ecology helps decide how far the virus can reprogram immunity.

Why does it matter?
PMN-MDSCs show up mainly in severe COVID-19.
You don’t see this in the same way with flu.
SARS-CoV-2 has a unique ability to paralyze immunity.

Implications.
Biomarkers - LOX-1+, PD-L1+ neutrophils could help flag risk of severe disease.
Therapy.
PD-1/PD-L1 blockade is tempting - but carries the danger of unleashing uncontrolled inflammation.

And the bigger picture - PMN-MDSCs aren’t unique to COVID.
They’re infamous in cancer - where they block T cells from attacking tumors.
So SARS-CoV-2 borrows from the tumor playbook.
It creates an environment where immunity is confused, restrained, and ineffective.

That parallel tells us COVID isn’t just pneumonia.
This virus taps into deep immune programs - the same ones that decide whether the body clears a tumor, or lets it grow.

This mechanism may also explain why some patients deteriorate so fast - even without massive early inflammation.
An immunosuppressive wave can follow the inflammatory one, tilting the system into collapse.

After COVID, some patients show a lingering exhausted T cell profile and elevated MDSCs for weeks or months.
That means reduced immune surveillance - not only against the virus, but also against early tumors or precancerous cells.

Studies report increased PD-L1+ and LOX-1+ neutrophils months after infection - in both severe cases and Long COVID.
This persistence may be part of why the immune shadow of SARS-CoV-2 lasts so long.

So the sharper question is -
If a virus can briefly create a cancer-like immune environment,
what does that mean for long-term immune balance, and the risk of persistent consequences?

And remember - this is just one of the virus’s tricks.
SARS-CoV-2 also -
blocks the interferon alarm (Nsp1, ORF6),
silences MHC-I to hide from T cells (ORF8),
and - turns neutrophils into suppressors.

The result isn’t weakness - it’s disorganization.
Some parts of the immune system go into overdrive, others are silenced.
That’s why COVID can be both inflammatory and immunosuppressive at the same time - the perfect setup for severe disease and lasting damage.

Hsieh at al., SARS-CoV-2 induces neutrophil degranulation and differentiation into myeloid-derived suppressor cells associated with severe COVID-19. pubmed.ncbi.nlm.nih.gov/40397714/

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