Enhancement of SARS-CoV-2 Infection via Crosslinking of Adjacent Spike Proteins by N-Terminal Domain-Targeting Antibodies

The study published in Viruses journal provides new insights into the interaction between the spike protein of SARS-CoV-2 and certain human antibodies. These antibodies target the N-terminal domain (NTD) of the spike protein, which is a site away from where the virus binds to the host cell’s ACE2 receptor. Interestingly, these NTD-targeting infection-enhancing antibodies (NIEAs) were found to augment the virus’s ability to bind ACE2, thus enhancing infection. This effect is notable because it occurs independently of the antibody’s crystallizable fragment (Fc) region, differentiating it from other known antibody-dependent enhancement (ADE) mechanisms​​​​.

Key Findings:

  1. Spike-Spike Crosslinking by NIEAs: The study proposes that NIEAs enhance SARS-CoV-2 infection by crosslinking adjacent spike proteins. This hypothesis was formed based on evidence from six different antibodies that were shown to enhance ACE2 binding in vitro. These antibodies compete with each other for binding to a specific patch on the spike protein’s NTD, which is distant from the spike-ACE2 interface. The crosslinking hypothesis was supported by Cryo-EM studies, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry (HDX-MS)​​.
  2. Structural Dynamics of the NIEA-Spike Interface: To understand the interaction between NIEAs and the spike protein at an atomic level, the researchers performed molecular dynamics (MD) simulations using fragment antigen-binding (Fab) regions instead of full antibodies. These simulations showed that the binding of antibodies to the spike protein stabilizes specific loops in the NTD, which are part of the overlapping epitope for NIEAs​​.
  3. Direct Evidence of Crosslinking: Electron microscopy (EM) was used to provide direct evidence of the crosslinking model. When IgG NIEAs were mixed with full-length spikes, the proteins aggregated, presumably due to extended crosslinking facilitated by the three enhancing epitopes on each spike trimer. This was further supported by observations of IgG antibodies in the presence of monomeric spike NTDs, which formed only NTD-NIEA-NTD trimers consistent with the proposed model​​.

Implications and Conclusion:

  • The study advances our understanding of the unique mechanisms of ADE, especially in the context of COVID-19. It suggests that NIEAs induce a novel form of ADE by crosslinking spike proteins, potentially affecting the receptor-binding domain’s (RBD) transition from the “down” to “up” state.
  • These findings raise important considerations for COVID-19 therapeutics and vaccines, as antibodies generated through vaccination or therapeutic antibodies may have the potential to cause ADE.
  • The researchers highlighted the need for future investigations into the impact of NIEAs on virus behavior and the implications for therapeutic and vaccine development​​.

This study not only deepens our understanding of the molecular interactions involved in SARS-CoV-2 infection but also opens new avenues for exploring the effects of antibody responses in the context of COVID-19.

Read More: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10747171/

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