Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein

SARS-CoV-2 infection is a major global public health concern with incompletely understood pathogenesis. The SARS-CoV-2 spike (S) glycoprotein comprises a highly conserved free fatty acid binding pocket (FABP) with unknown function and evolutionary selection advantage(1,2). Deciphering FABP impact on COVID-19 progression is challenged by the heterogenous nature and large molecular variability of live virus. Here we create synthetic minimal virions (MiniVs) of wild-type and mutant SARS-CoV-2 with precise molecular composition and programmable complexity by bottom-up assembly. MiniV-based systematic assessment of S free fatty acid (FFA) binding reveals that FABP functions as an allosteric regulatory site enabling adaptation of SARS-CoV-2 immunogenicity to inflammation states via binding of pro-inflammatory FFAs. This is achieved by regulation of the S open-to-close equilibrium and the exposure of both, the receptor binding domain (RBD) and the SARS-CoV-2 RGD motif that is responsible for integrin co-receptor engagement. We find that the FDA-approved drugs vitamin K and dexamethasone modulate S-based cell binding in an FABP-like manner. In inflammatory FFA environments, neutralizing immunoglobulins from human convalescent COVID-19 donors lose neutralization activity. Empowered by our MiniV technology, we suggest a conserved mechanism by which SARS-CoV-2 dynamically couples its immunogenicity to the host immune response. Staufer et al. provide a protocol for preparation of synthetic minimal virions (MiniV) of SARS-CoV-2, mimicking viral structure and allowing for precise investigation of receptor binding mechanism. They find that the highly conserved free fatty acid binding pocket (FABP) can function as an allosteric regulator, enabling adaptation of immunogenicity via binding of proinflammatory free fatty acids and mediating the spike open to-closed equilibrium.

Automated summary

This study investigates the mechanism of SARS-CoV-2 spike protein binding to fatty acids using synthetic minimal virions. The study reveals that the fatty acid binding pocket of the spike protein can act as an allosteric regulator, allowing the virus to adapt its immunogenicity in response to inflammation. The study also demonstrates that certain FDA-approved drugs can modulate cell binding of the spike protein in a similar manner to the fatty acid binding pocket. The findings provide insights into how SARS-CoV-2 dynamically interacts with the host immune response.