COVID-19 is often described as an inflammatory disease.
But new research shows SARS-CoV-2 goes deeper.
It alters regulatory layers inside cells at the RNA level, weakening antiviral defense from within.🧵
Thanks @NFMai @RWittenbrink
But new research shows SARS-CoV-2 goes deeper.
It alters regulatory layers inside cells at the RNA level, weakening antiviral defense from within.🧵
Thanks @NFMai @RWittenbrink
https://twitter.com/rwittenbrink/status/2001343376445383070
Cells contain long non-coding RNAs (lncRNAs).
They don’t make proteins - they act as control hubs, coordinating immune signals, especially interferon (IFN) responses.
They don’t make proteins - they act as control hubs, coordinating immune signals, especially interferon (IFN) responses.
RNA function isn’t fixed.
It can be fine tuned by a chemical mark called m6A methylation, which changes RNA shape, interactions, and behavior - without changing RNA levels.
It can be fine tuned by a chemical mark called m6A methylation, which changes RNA shape, interactions, and behavior - without changing RNA levels.
And the study shows that SARS-CoV-2 systematically reshapes m6A marks on lncRNAs involved in interferon signaling, the cell’s main antiviral alarm system.
The most affected lncRNAs include UCA1, NORAD, and GAS5 - well known regulators of IFN pathways, STAT signaling, and antiviral gene expression.
Importantly, this is not immune shutdown.
It’s immune misalignment - interferon responses are present, but delayed, weakened, or poorly coordinated.
It’s immune misalignment - interferon responses are present, but delayed, weakened, or poorly coordinated.
This matches a one of key COVID-19 paradox.
Early and efficient viral replication, followed by inflammation that arrives too late for effective antiviral control.
Early and efficient viral replication, followed by inflammation that arrives too late for effective antiviral control.
A striking finding - one of these RNAs (UCA1) can directly bind the SARS-CoV-2 genome.
These interactions are strong - and conserved even in Omicron.
These interactions are strong - and conserved even in Omicron.
This suggests lncRNAs are not just collateral damage, but may be actively involved in viral RNA-RNA interactions.
Rather than attacking immunity head-on, the virus seems to retune immune regulation, making it function less effectively.
Rather than attacking immunity head-on, the virus seems to retune immune regulation, making it function less effectively.
Why does this matter?
Because changes in RNA regulation don’t necessarily reset quickly after infection. This isn’t destruction - it’s a shifted regulatory state.
lncRNAs regulate not only interferons, but also inflammation, cellular stress, mitochondrial function, and DNA repair.
Their dysregulation has broad biological consequences.
Because changes in RNA regulation don’t necessarily reset quickly after infection. This isn’t destruction - it’s a shifted regulatory state.
lncRNAs regulate not only interferons, but also inflammation, cellular stress, mitochondrial function, and DNA repair.
Their dysregulation has broad biological consequences.
This can lead to a state that doesn’t look like classic immunodeficiency, but rather functional immune impairment - the system is there, but it doesn’t work optimally.
This is where long COVID comes into focus.
This is where long COVID comes into focus.
Low-grade inflammation, impaired antiviral responses, slow recovery - these patterns fit well with long-lasting regulatory dysregulation, not necessarily ongoing infection.
Repeated infections matter here.
Each new exposure may hit the same regulatory RNA nodes, rather than allowing the system to fully reset.
This differs from most respiratory viruses, where immune regulation usually returns to baseline after clearance.
Each new exposure may hit the same regulatory RNA nodes, rather than allowing the system to fully reset.
This differs from most respiratory viruses, where immune regulation usually returns to baseline after clearance.
Cristina M Peter at al., SARS-CoV-2 reshapes m6A methylation in long noncoding RNAs of human lung cells. academic.oup.com/narmolmed/arti…
Why mention HIV in this context?
Because with HIV it’s long been shown that the virus doesn’t weaken immunity only by exhaustion or cell loss - but by directly interfering with RNA regulation inside cells.
Because with HIV it’s long been shown that the virus doesn’t weaken immunity only by exhaustion or cell loss - but by directly interfering with RNA regulation inside cells.
HIV heavily exploits RNA regulation.
The viral protein Tat binds host RNAs, disrupts rRNA biogenesis, alters ribosome availability and function
The viral protein Tat binds host RNAs, disrupts rRNA biogenesis, alters ribosome availability and function
HIV RNA itself also plays an active role.
It interacts with host lncRNAs
reshapes RNA-binding protein networks
effectively rewiring the infrastructure of cellular regulation.
It interacts with host lncRNAs
reshapes RNA-binding protein networks
effectively rewiring the infrastructure of cellular regulation.
Changes in key lncRNAs are well documented, including
NEAT1, MALAT1, GAS5,
and other RNAs involved in interferon signaling.
NEAT1, MALAT1, GAS5,
and other RNAs involved in interferon signaling.
And these effects persist even under effective ART.
Despite suppressed viremia, patients show lasting epigenetic marks, altered IFN signaling, chronic immune activation
Despite suppressed viremia, patients show lasting epigenetic marks, altered IFN signaling, chronic immune activation
Part of this dysregulation is stable, cell-inherited, difficult to reverse. This is not just about viral presence, but about a rewritten regulatory state of cells.
That’s why HIV is associated with
accelerated biological aging
higher cardiovascular risk
neurodegenerative and immune disorders
even with good long-term treatment.
accelerated biological aging
higher cardiovascular risk
neurodegenerative and immune disorders
even with good long-term treatment.
We should have learned long ago from the biology of chronic viruses.
HIV, EBV, CMV already taught us that viruses don’t need to destroy cells to cause long-term harm - reprogramming regulation is enough.
The current SARS2 approach is unsustainable.
@szupraha @ZdravkoOnline @adamvojtech86
HIV, EBV, CMV already taught us that viruses don’t need to destroy cells to cause long-term harm - reprogramming regulation is enough.
The current SARS2 approach is unsustainable.
@szupraha @ZdravkoOnline @adamvojtech86
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