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

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Staufer,  Oskar
Cellular Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

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Hernandez Bücher,  Jochen Estebano
Cellular Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

/persons/resource/persons272029

Relimpio,  Ana Yagüe
Cellular Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

/persons/resource/persons272031

Macher,  Meline
Cellular Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

/persons/resource/persons225871

Fabritz,  Sebastian
Chemical Biology, Max Planck Institute for Medical Research, Max Planck Society;

/persons/resource/persons272033

Dietz,  Hendrik
Max Planck Institute for Medical Research, Max Planck Society;

/persons/resource/persons75354

Cavalcanti Adam,  Elisabetta Ada
Cellular Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

/persons/resource/persons84351

Platzman,  Ilia
Cellular Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

/persons/resource/persons76135

Spatz,  Joachim P.
Cellular Biophysics, Max Planck Institute for Medical Research, Max Planck Society;

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Citation

Staufer, O., Gupta, K., Hernandez Bücher, J. E., Kohler, F., Sigl, C., Singh, G., et al. (2022). Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein. Nature Communications, 13: 868, pp. 1-13. doi:10.1038/s41467-022-28446-x.


Cite as: http://hdl.handle.net/21.11116/0000-000A-3D09-9
Abstract
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 advantage1,2. 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.