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

    Journal: Nat. Commun., Volume 13, FEB 14

    Authors: Staufer, Oskar; Gupta, Kapil; Buecher, Jochen Estebano Hernandez; Kohler, Fabian; Sigl, Christian; Singh, Gunjita; Vasileiou, Kate; Relimpio, Ana Yague; Macher, Meline; Fabritz, Sebastian; Dietz, Hendrik; Adam, Elisabetta Ada Cavalcanti; Schaffitzel, Christiane; Ruggieri, Alessia; Platzman, Ilia; Berger, Imre; Spatz, Joachim P.

    Organizations: Heidelberg Bioscience International Graduate School; Max Planck School Matter to Life; Federal Ministry of Education and Research of Germany [13XP5073A]; MaxSynBio Consortium - Federal Ministry of Education and Research of Germany; MaxSynBio Consortium - Max Planck Society; Volkswagen Stiftung; German Science Foundation [SFB1129, 240245600-SFB1129]; Germany's Excellence Strategy via the Excellence Cluster 3D Matter Made to Order [EXC-2082/1-390761711]; Elizabeth Blackwell Institute for Health Research; EPSRC Impact Acceleration Account University of Bristol [EP/R511663/1]; Deutsche Forschungsgemeinschaft via the Gottfried-Wilhelm-Leibniz Program; European Research Council Consolidator Grant [724261]; Max Planck School Matter to Life (BMBF); Max Planck School Matter to Life (Max Planck Society); EU FET Open Project Virofight [899619]; UK Research and Innovation (UKRI) through the Bristol Synthetic Biology Centre BrisSynBio [BB/L01386X/1]; Wellcome Trust [210701/Z/18/Z, 106115/Z/14/Z]

    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.
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