by Parth Sarthi Sen Gupta
This cover art depicts SARS-CoV-2’s novel immune escape strategy, where Spike-NTD binds with the host fibrinogen, shielding the virus from NTD-directed antibodies and facilitating immune evasion. Credit: Parth Sarthi Sen Gupta
As scientists, we often think we understand a virus—its structure, its tricks, the way it moves through the body. But every once in a while, we stumble upon something unexpected—something that completely changes the way we see an infection.
I have spent years studying the molecular tactics of viruses—how they invade, replicate, and most intriguingly, how they evade our immune system. Some strategies are well documented: antigenic drift, glycan shielding, immune suppression. But every so often, we stumble upon a novel mechanism that redefines our understanding of viral pathogenesis.
A recent finding in Nature showed that the spike protein of SARS-CoV-2 binds with fibrinogen, leading to thrombo-inflammation. This raises a fundamental question: Why does the virus need to bind with fibrinogen? Could this interaction provide an evolutionary advantage to the virus? Could this be the reason behind post-COVID heart attack cases?
In our recent study, published in ACS Pharmacology & Translational Science, we found that SARS-CoV-2, the virus that causes COVID-19, has a sneaky way of escaping immune detection. It binds to fibrinogen, a key protein involved in blood clotting with stronger affinity than antibodies. This interaction not only helps the virus evade immune cells but may also contribute to the dangerous clotting issues seen in severe COVID-19 cases. This finding could change how we think about the virus and how we treat it.
The mystery of COVID-19, blood clots and immune escape
When COVID-19 first emerged, most people focused on its impact on the lungs. But soon, doctors started reporting something unusual—many critically ill patients were developing blood clots, leading to strokes, heart attacks and organ failure. This was strange because viral infections don’t typically cause widespread clotting issues.
For months, researchers tried to understand why. Some thought it was due to excessive inflammation, while others suspected direct viral damage to blood vessels. But no one had a clear answer.
That’s when we decided to look at fibrinogen, one of the most important proteins involved in blood clotting. Our study revealed that the γ-chain demonstrates a higher binding affinity for the NTD domain compared to the neutralizing antibodies, providing striking insights and suggesting that the virus had evolved a mechanism to preferentially bind to fibrinogen rather than the neutralizing antibodies.
Fibrinogen acts like glue, helping platelets stick together to form clots when needed. But what if SARS-CoV-2 had found a way to exploit this system? We proposed the Dual Immune Evasion Strategy of the virus:
- Mutating the receptor binding domain (RBD) of the spike protein: The virus introduces mutations in the RBD region of the spike protein to escape neutralizing antibodies targeted against it.
- Fibrinogen binding to N-terminal domain (NTD) of spike: To protect the more conserved NTD, the virus interacts with fibrinogen, protecting the NTD region from antibody recognition.
This dual strategy of SARS-CoV-2 helps it to maintain infectivity while escaping the host immunity.
A) 3D conformation of the spike NTD bound to the γ-chain of fibrinogen (docked conformation), along with S2M28 (PDB ID: 7LY0) and SARS2-57 (PDB ID: 7SWW). B) Surface diagram showing the binding of spike NTD to the γ-chain of fibrinogen, S2M28, and SARS2-57, highlighting the similar interacting orientations of the three. C) MMGBSA binding free energy comparison for the γ-chain of fibrinogen and neutralizing antibodies (S2M28, SARS2-57, and 4A8). Credit: ACS Pharmacology & Translational Science (2025). DOI: 10.1021/acsptsci.5c00122
Implications for immune evasion and pathogenesis
Viruses are masterful at exploiting host systems. HIV hides within host cells; influenza frequently mutates its surface proteins; and now, we see that SARS-CoV-2 might be leveraging fibrinogen as a molecular cloak.
Fibrinogen is known to interact with immune cells, particularly neutrophils and macrophages, through integrin receptors. By binding fibrinogen, the spike protein might be interfering with normal immune signaling, preventing efficient recognition and clearance of the virus. This could contribute to prolonged viral persistence in some patients, leading to chronic or severe disease.
Additionally, this interaction might explain why some COVID-19 patients develop severe inflammatory and coagulation-related complications. If spike-fibrinogen binding alters clotting dynamics, it could be a driving factor behind the thrombotic events seen in critical cases. Understanding this mechanism gives us a new target for potential therapeutic interventions.
Looking forward: What this means for treatment and prevention
Our finding raises important questions: Can we block the spike-fibrinogen interaction to reduce disease severity? Could fibrinogen levels serve as a biomarker for predicting COVID-19 complications? And, most critically, does this mechanism play a role in other emerging variants?
One possible therapeutic avenue is developing small molecules or monoclonal antibodies that disrupt spike-fibrinogen binding. By preventing this interaction, we might be able to restore normal immune function and reduce clotting risks in severe patients.
Additionally, our findings emphasize the need to look beyond traditional receptor interactions when studying viral immune evasion. If SARS-CoV-2 can manipulate host proteins like fibrinogen, what other molecular partnerships remain undiscovered? This study serves as a stepping stone for deeper investigations into the interplay between viral proteins and host immune factors.
A personal perspective
Scientific discovery is often a mix of persistence and serendipity. When we began this study, we weren’t looking for an immune evasion mechanism—we were searching for the reason behind the fibrinogen binding. But as the data unfolded, it became clear that we had uncovered something bigger.
As a computational biologist, I have always been fascinated by the unseen molecular dialogues between viruses and host cells. The fact that a virus can exploit a key clotting protein to evade immune detection is both astonishing and humbling. It’s a reminder that, despite our scientific advancements, nature still holds secrets waiting to be unraveled.
Conclusion
Our study on the spike-fibrinogen interaction reveals a novel immune escape strategy of SARS-CoV-2, with potential implications for disease severity and treatment. By binding fibrinogen, the virus not only disrupts normal clotting but may also evade immune surveillance, contributing to prolonged infection and severe inflammatory responses.
Understanding these molecular interactions is crucial for developing targeted therapies. As we continue to study the intricate battle between SARS-CoV-2 and the immune system, one thing is clear: The virus is a formidable opponent, but with deeper insight, we can develop strategies to counter its tricks.
Science, at its core, is about uncovering the unknown. This discovery is just one piece of the puzzle, but it brings us closer to understanding—and ultimately defeating—the virus that has reshaped our world.
This story is part of Science X Dialog, where researchers can report findings from their published research articles. Visit this page for information about Science X Dialog and how to participate.
More information: Saroj Kumar Panda et al, Spike Protein–Fibrinogen Interaction: A Novel Immune Evasion Strategy of SARS-CoV-2?, ACS Pharmacology & Translational Science (2025). DOI: 10.1021/acsptsci.5c00122
Dr. Parth Sarthi Sen Gupta is an associate professor in the School of Biosciences and Bioengineering, D Y Patil International University. He has published more than 50 research articles and book chapters in reputed peer reviewed journals. He is a computational biologist working on designing and developing therapeutics against various diseases. His research work on COVID-19 has been highlighted by various national and international news agencies and recognized by world health organizations.
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