The host protein fibrinogen has been found to interact with the N-terminal domain (NTD) of the spike protein in SARS-CoV-2 as an immune evasion strategy adopted by the virus to outsmart the NTD targeted neutralizing antibodies.

The journey of the COVID-19 virus, which emerged in early 2019, has been nothing short of remarkable as it evolved and spread globally. Spike protein of the virus, which plays a critical role in its entry into human cells, became the focus of major scientific research. Specifically, the receptor-binding domain (RBD) of the spike antigen received special attention as it has a direct interaction with the human ACE2 receptor, accelerating the virus to infect host cells. As such, neutralizing antibodies against the RBD appeared to be the dominant defense system.

Antibody Binding Sites and Immune Evasion

The immune system targets the spike protein to neutralize the virus. Antibodies mainly bind epitopes in the receptor-binding domain (RBD) and N-terminal domain (NTD). The RBD of the spike protein is known for its high mutation rate, permitting the virus to alter its structure to evade the neutralizing antibodies. On the other hand, the NTD has been considered more conserved, suggesting limited capacity for mutation without compromising viral fitness.

As these neutralizing antibodies targeted the RBD, the virus adapted by evolving into different variants. These mutations within the RBD permitted the virus to reduce its affinity for these neutralizing antibodies, essentially weakening their ability to block infection. This evolution was a strategic move by the virus, allowing it to evade immune responses while simultaneously strengthening its binding affinity for ACE2, maintaining its infectivity toward human cells. However, the reason behind the immune evasion of the virus from the NTD targeted neutralizing antibodies was elusive until now.

Interaction with Fibrinogen

Fibrinogen, the precursor to fibrin, is a central component of blood clots and is abundantly deposited in the lungs and brains of COVID-19 patients. Its levels correlate with disease severity and predict post-COVID-19 cognitive deficits. Recently, Ryu et al. demonstrated that fibrinogen binds directly to the SARS-CoV-2 spike protein, forming pro-inflammatory clots that exacerbate systemic inflammation and neuropathology. This interaction is mediated by the N-terminal domain (NTD) of the spike protein in SARS-CoV-2.

Dual Immune Evasion Strategy

Considering the need of the virus to evade the immune system against neutralizing antibodies, a plausible hypothesis emerges:

This dual strategy might allow SARS-CoV-2 to maintain its infectivity while evading the immune responses.

Supporting Evidence

At first glance, the interaction between fibrinogen and the spike protein’s NTD domain seemed curious. Why would the virus, which had already evolved to escape antibody recognition, engage with another host protein? A deeper investigation suggested a plausible answer: by interacting with fibrinogen, the virus might be employing a clever tactic to avoid immune detection, specifically the neutralizing antibodies that target the NTD.

The results of the research suggest that the γ-chain of fibrinogen demonstrates a higher binding affinity for the NTD domain compared to the neutralizing antibodies, indicating that the virus had evolved a mechanism to preferentially bind to fibrinogen to escape from the neutralizing antibodies. it has been also observed that the fibrinogen is not only binding strongly to the NTD of spike protein but also blocking the site to protect against the antibodies. This discovery raised intriguing questions about the virus’s ability to self-protect itself against immune responses.

It seemed that now the virus had found a way to protect itself from both the host immune system and the antibodies targeting the NTD domain. In essence, the virus was not only evading immune detection through mutations in the RBD but was also using the NTD domain’s interaction with fibrinogen as another shield against neutralizing antibodies. These adopted strategies of the virus for the immune evasion, i.e., mutating the RBD for ACE2 binding as well escaping from RBD-directed antibodies and using the more conserved NTD to engage with the fibrinogen, highlighted the remarkable adaptability of the virus and its capacity to outsmart the immune system at multiple levels.

This finding about the role of fibrinogen in facilitating the survival of the virus is a significant step forward in understanding how SARS-CoV-2 manages to persist and evade immune defenses. It also opens up new areas for the research for the scientists to explore how this unique interaction between the spike protein and fibrinogen could be utilized for future therapeutic advancements or vaccine designs. What once started as a race against the clock to understand the mechanisms of infection during the pandemic has now turned into a more complex puzzle, one where the ability of virus to outwit the immune system continues to evolve and challenges our scientific understanding.

Conclusion and Future Perspective

The binding of the NTD of spike protein to fibrinogen demonstrates a sophisticated mechanism of immune evasion by the SARS-CoV-2. This interaction not only shields the virus from neutralizing antibodies but also contribute to the thrombotic events observed in the post-COVID-19 patients. To better understand and elucidate the mechanism for advance therapeutics and vaccines, more research is needed. Further, the targeted therapies that can disrupt this interaction, thereby enhancing the efficacy of immune responses against the virus is of utmost need.