Thread by @ZdenekVrozina

SARS-CoV-2 is not just another respiratory virus.
It has evolutionarily selected features that actively manipulate innate immunity - similar to viruses like HIV, EBV, or CMV.
A new study in iScience shows how.🧵

https://twitter.com/vipintukur/status/1944562639293808742

What are formyl peptide receptors (FPRs)?
They’re innate immune sensors on neutrophils and other immune cells.
They detect signs of infection or damage.
Key types
FPR1: strongly pro-inflammatory
FPR2: dual, context-dependent
FPR3: poorly understood, but active in viral immunity

The new study tested 80 synthetic peptides from the Omicron spike protein.
It found:
10 activated FPR1
9 activated FPR2
30 (!) activated FPR3
Several triggered immune responses in primary human neutrophils

FPR1 + neutrophils = inflammatory firestorm.
FPR1 is highly expressed on neutrophils and triggers:
migration
NET formation
MMP-9 release
inflammatory signaling
Dysregulated FPR1 activation = tissue damage, thrombosis, autoimmunity - seen in severe COVID-19.

The spike protein contains both activators and inhibitors of FPR1.
Some peptides activate FPR1 = inflammation
Others, especially from the conserved MPR region, block FPR1 and blunt neutrophil responses.
The virus toggles immune signaling on and off.

Example: the SARS-CoV-2 peptide WPWYVWL (from the MPR region) competitively inhibits FPR1.
Other peptides (mainly from mutagenic spike regions) activate FPRs and trigger:
calcium signaling
chemotaxis
NETosis
MMP-9 release

Sound familiar?
HIV-1 uses gp41 and gp120 fragments to modulate FPRs
FPR2 is even a co-receptor for HIV entry in some models
FPR1 ligands from HIV (like T20/DP178) show striking parallels to SARS-CoV-2 MPR peptides
SARS-CoV-2 is playing the same evolutionary game.

The consequences?
Severe COVID-19 - driven by dysregulated neutrophil-FPR1 activation
Post-COVID syndrome - possible immune rewiring
Variant evolution - aided by immune evasion via FPR modulation
Reinfections - immune confusion from mixed FPR signaling

SARS-CoV-2 manipulates the first lines of immune defense - just like HIV, EBV, CMV.

This is not “just the flu.”
SARS-CoV-2 shows features of sophisticated viral immune manipulation:
it uses selected fragments of the spike protein
it targets the initial signaling pathways of the immune system
it switches between triggering inflammation and suppressing it

This kind of research changes how we think about “respiratory” viruses.
It points to:
FPRs as immune bottlenecks
Potential for FPR-targeted therapies
Viral evolution shaped by receptor interaction - not just ACE2

Heilmann et al., 2025, iScience, 2025. Fragments of viral surface proteins modulate innate immune responses via formyl peptide receptors. cell.com/iscience/fullt…