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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 advantage1,2. Deciphering FABP impact on C...

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Main Authors: Staufer, Oskar (Author) , Gupta, Kapil (Author) , Hernandez Bücher, Jochen Estebano (Author) , Köhler, Fabian (Author) , Sigl, Christian (Author) , Singh, Gunjita (Author) , Vasileiou, Kate (Author) , Yagüe Relimpio, Ana (Author) , Macher, Meline (Author) , Fabritz, Sebastian (Author) , Dietz, Hendrik (Author) , Cavalcanti-Adam, Elisabetta A. (Author) , Schaffitzel, Christiane (Author) , Ruggieri, Alessia (Author) , Platzman, Ilia (Author) , Berger, Imre (Author) , Spatz, Joachim P. (Author)
Format: Article (Journal)
Language:English
Published: 14 February 2022
In: Nature Communications
Year: 2022, Volume: 13, Pages: 1-13
ISSN:2041-1723
DOI:10.1038/s41467-022-28446-x
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-022-28446-x
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-022-28446-x
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Author Notes:Oskar Staufer, Kapil Gupta, Jochen Estebano Hernandez Bücher, Fabian Kohler, Christian Sigl, Gunjita Singh, Kate Vasileiou, Ana Yagüe Relimpio, Meline Macher, Sebastian Fabritz, Hendrik Dietz, Elisabetta Ada Cavalcanti Adam, Christiane Schaffitzel, Alessia Ruggieri, Ilia Platzman, Imre Berger & Joachim P. Spatz
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Summary: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.
Item Description:Gesehen am 30.03.2022
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-022-28446-x

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