Thread by @ZdenekVrozina

A new Russian review in IJMS shows how SARS-CoV-2 reshapes the epigenome - weaving together known mechanisms into something deeper.
It’s not just long COVID.
It’s a virus that rewrites the factory that makes immune cells - the bone marrow🧵

https://twitter.com/harryspoelstra/status/1982390714328637626

Zolotarenko puts special emphasis on this point.
The changes don’t appear in mature immune cells -
they start in their progenitors.
These hematopoietic precursors are born misprogrammed inside the marrow.

That’s why, even after infection clears, the body keeps producing confused immune cells.
The virus is gone, but its instructions remain.
An epigenetic imprint continues to guide new cells months later.

Key points:
The immune imprint in bone marrow.
Cytokines like IL-6, TNF, and GM-CSF don’t stay in the blood.
They penetrate the marrow and rewrite the genetic instructions of stem cells.

IL-6 acts as an epigenetic recorder.
It modifies DNA methylation and histone marks in hematopoietic stem cells (HSPCs).
The marrow remembers the infection
and keeps making hyper-reactive cells long after the virus is gone.

ORF8 - the virus with a key to our DNA.
SARS-CoV-2 reaches deep into the nucleus.
Its ORF8 protein mimics a human histone (H3) and changes which genes can be read.
It doesn’t destroy DNA - it rewrites access permissions.

That silences interferon pathways from within -
the virus stays, but the alarms go quiet.
It’s a pattern we know from latent viruses like EBV or CMV.
SARS-CoV-2 may not hide, but it lingers through memory.

Epigenetic aging.
After infection, cellular epigenetic clocks speed up.
Cells behave as if they’re older -
more inflammation, slower repair, less resilience.

The rhythm is lost.
The immune system overreacts when it should rest,
and stays silent when it should defend.
It’s aging not by years, but by how cells interpret their own code.

The N protein – a quiet remodeler of DNA
Protein N binds to chromatin and shifts nucleosomes - the anchors that organize DNA.
That changes which genes stay open and which fall silent.

It touches genes for immunity, coagulation, and vascular stability.
Imagine someone moving chapters in a book -
the words are the same, but the story changes.
Result - microclots, fatigue, barrier damage.

miRNA.
Cells regulate balance using small RNAs - miRNAs.
During COVID, many are lost.
Inflammatory circuits stay on, as if the car lost its brakes.

Meanwhile, the virus makes its own miRNA-like fragments that mimic ours.
They silence key antiviral genes (IRF7, BATF2).
The body hears the alarm - but no one picks up the phone.
Inflammation runs on, even without virus.

Can the epigenome be erased?
Epigenetic change has one advantage - it’s reversible.
Zolotarenko discusses epigenetic reversion -
resetting cell programs using so-called epidrugs.

HDAC and DNMT inhibitors, already in cancer and neuro research,
don’t attack the virus but the imprint it leaves behind.
The goal isn’t to kill the virus - it’s to rehabilitate cellular memory.

IL-6.
In the acute phase, IL-6 protects.
But if it lingers, it starts writing to memory.
It alters DNA methylation and histone profiles in bone marrow.
A short-term defense becomes a long-term rewrite.

IL-6 as a molecular chronicler of infection.
What it records during fever can echo for months.
Block it too early - you hinder defense.
Block it too late - you risk embedding the imprint.

Sum:
COVID-19 is not an ordinary infection.
It’s a virus that reaches the body’s command layer - the epigenome -
and rewires how immunity forms and behaves.

Zolotarenko puts it clearly.
SARS-CoV-2 leaves an epigenetic latency.
It doesn’t stay active -
but the body keeps carrying its instructions.
New cells are born already carrying the memory of infection.

Unlike typical viruses that visit and leave,
COVID-19 acts like an architect -
it redraws the blueprint of the house and walks away before we notice.

Biologically, we’ve seen similar outcomes with other latent viruses
immune deregulation
altered responses to new infections
higher risk of autoimmunity and some cancers.

Zolotarenko et al., COVID-19 Hijacking of the Host Epigenome: Mechanisms, Biomarkers and Long-Term Consequences. International Journal of Molecular Sciences, 2025. mdpi.com/1422-0067/26/2…

Repeated SARS-CoV-2 infections mean repeated hits to the immune and epigenetic systems.
When a virus rewires how our cells read their own DNA, it’s not just a personal issue but population biology.
These long-term shifts deserve public health monitoring.

This isn’t alarmism - it’s realism.
COVID-19 isn’t a brief episode, but a virus with a long shadow.
And to understand its legacy,
we must learn to read the language it left inside our immune system.