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

Author

Listed:
  • Oskar Staufer

    (Max Planck Institute for Medical Research
    University of Heidelberg
    University of Bristol
    Max Planck School Matter to Life)

  • Kapil Gupta

    (University of Bristol
    University of Bristol)

  • Jochen Estebano Hernandez Bücher

    (Max Planck Institute for Medical Research
    University of Heidelberg)

  • Fabian Kohler

    (Technical University of Munich)

  • Christian Sigl

    (Technical University of Munich)

  • Gunjita Singh

    (University of Bristol)

  • Kate Vasileiou

    (University of Bristol)

  • Ana Yagüe Relimpio

    (Max Planck Institute for Medical Research
    University of Heidelberg)

  • Meline Macher

    (Max Planck Institute for Medical Research
    University of Heidelberg
    Max Planck School Matter to Life)

  • Sebastian Fabritz

    (Max Planck Institute for Medical Research)

  • Hendrik Dietz

    (Max Planck School Matter to Life
    Technical University of Munich)

  • Elisabetta Ada Cavalcanti Adam

    (Max Planck Institute for Medical Research
    Max Planck School Matter to Life)

  • Christiane Schaffitzel

    (University of Bristol
    University of Bristol
    Halo Therapeutics Ltd, Science Creates, Albert Road St. Philips Central)

  • Alessia Ruggieri

    (University of Heidelberg)

  • Ilia Platzman

    (Max Planck Institute for Medical Research
    University of Heidelberg
    University of Bristol)

  • Imre Berger

    (University of Bristol
    University of Bristol
    University of Bristol
    Halo Therapeutics Ltd, Science Creates, Albert Road St. Philips Central)

  • Joachim P. Spatz

    (Max Planck Institute for Medical Research
    University of Heidelberg
    University of Bristol
    Max Planck School Matter to Life)

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.

Suggested Citation

  • Oskar Staufer & Kapil Gupta & Jochen Estebano Hernandez Bücher & Fabian Kohler & Christian Sigl & Gunjita Singh & Kate Vasileiou & Ana Yagüe Relimpio & Meline Macher & Sebastian Fabritz & Hendrik Diet, 2022. "Synthetic virions reveal fatty acid-coupled adaptive immunogenicity of SARS-CoV-2 spike glycoprotein," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28446-x
    DOI: 10.1038/s41467-022-28446-x
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    1. Oskar Staufer & Gösta Gantner & Ilia Platzman & Klaus Tanner & Imre Berger & Joachim P. Spatz, 2022. "Bottom-up assembly of viral replication cycles," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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