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.
| Original language | English |
|---|---|
| Article number | 868 |
| Journal | Nature Communications |
| Volume | 13 |
| Issue number | 1 |
| Early online date | 14 Feb 2022 |
| DOIs | |
| Publication status | E-pub ahead of print - 14 Feb 2022 |
Bibliographical note
Funding Information:We would like to thank Sabine Grünewald for cell culture support, Isabelle Kajzar for critical discussion of the data, Ulrike Mersdorf for support in MiniV negative staining and TEM imaging and Mirko Cortese and Christopher J. Neufeldt (Molecular Virology Heidelberg) for sharing their expertise with SARS-CoV-2 infection. Some elements in the figures were created with BioRender.com. Support from the Heidelberg Bioscience International Graduate School and the Max Planck School Matter to Life is acknowledged by O.S. J.P.S. is the Weston Visiting Professor at the Weizmann Institute of Science and part of the excellence cluster CellNetworks at the University of Heidelberg. O.S. is the Meurer Visiting Professor at the University of Bristol. The Max Planck Society is appreciated for its general support by O.S., J.E.H.B., A.Y.R., M.M., S.F., E.A.C.A., I.P., J.P.S. J.P.S. and I.P. acknowledge funding from the Federal Ministry of Education and Research of Germany, Grant Agreement no. 13XP5073A, PolyAntiBak and the MaxSynBio Consortium, which is jointly funded by the Federal Ministry of Education and Research of Germany and the Max Planck Society. J.P.S. and I.P. also acknowledge the support from the Volkswagen Stiftung (priority call ‘Life?’). The German Science Foundation SFB1129 (project nr. 240245600-SFB1129 P15 to A.E.C.A and J.P.S. and P13 to A.R.) is acknowledged by E.A.C.A., A.R., and J.P.S. J.P.S acknowledges the support from Germany’s Excellence Strategy via the Excellence Cluster 3D Matter Made to Order (EXC-2082/1–390761711). This research received support from the Elizabeth Blackwell Institute for Health Research and the EPSRC Impact Acceleration Account EP/R511663/1 University of Bristol to C.S. and I.B., the Deutsche Forschungsgemeinschaft via the Gottfried-Wilhelm-Leibniz Program to H.D. and J.P.S., a European Research Council Consolidator Grant (#724261) to H.D., the Max Planck School Matter to Life (a joint program of BMBF and Max Planck Society) to O.S., M.M., H.D., and J.P.S., and the EU FET Open Project Virofight (#899619) to H.D. I.B. acknowledges support from UK Research and Innovation (UKRI) through the Bristol Synthetic Biology Centre BrisSynBio (BB/L01386X/1). C.S. and I.B. are Investigators of the Wellcome Trust (210701/Z/18/Z; 106115/Z/14/Z).
Funding Information:
We would like to thank Sabine Grünewald for cell culture support, Isabelle Kajzar for critical discussion of the data, Ulrike Mersdorf for support in MiniV negative staining and TEM imaging and Mirko Cortese and Christopher J. Neufeldt (Molecular Virology Heidelberg) for sharing their expertise with SARS-CoV-2 infection. Some elements in the figures were created with BioRender.com. Support from the Heidelberg Bioscience International Graduate School and the Max Planck School Matter to Life is acknowledged by O.S. J.P.S. is the Weston Visiting Professor at the Weizmann Institute of Science and part of the excellence cluster CellNetworks at the University of Heidelberg. O.S. is the Meurer Visiting Professor at the University of Bristol. The Max Planck Society is appreciated for its general support by O.S., J.E.H.B., A.Y.R., M.M., S.F., E.A.C.A., I.P., J.P.S. J.P.S. and I.P. acknowledge funding from the Federal Ministry of Education and Research of Germany, Grant Agreement no. 13XP5073A, PolyAntiBak and the MaxSynBio Consortium, which is jointly funded by the Federal Ministry of Education and Research of Germany and the Max Planck Society. J.P.S. and I.P. also acknowledge the support from the Volkswagen Stiftung (priority call ‘Life?’). The German Science Foundation SFB1129 (project nr. 240245600-SFB1129 P15 to A.E.C.A and J.P.S. and P13 to A.R.) is acknowledged by E.A.C.A., A.R., and J.P.S. J.P.S acknowledges the support from Germany’s Excellence Strategy via the Excellence Cluster 3D Matter Made to Order (EXC-2082/1–390761711). This research received support from the Elizabeth Blackwell Institute for Health Research and the EPSRC Impact Acceleration Account EP/R511663/1 University of Bristol to C.S. and I.B., the Deutsche Forschungsgemeinschaft via the Gottfried-Wilhelm-Leibniz Program to H.D. and J.P.S., a European Research Council Consolidator Grant (#724261) to H.D., the Max Planck School Matter to Life (a joint program of BMBF and Max Planck Society) to O.S., M.M., H.D., and J.P.S., and the EU FET Open Project Virofight (#899619) to H.D. I.B. acknowledges support from UK Research and Innovation (UKRI) through the Bristol Synthetic Biology Centre BrisSynBio (BB/L01386X/1). C.S. and I.B. are Investigators of the Wellcome Trust (210701/Z/18/Z; 106115/Z/14/Z).
Publisher Copyright:
© 2022, The Author(s).
Research Groups and Themes
- Bristol BioDesign Institute
- Covid19
- UNCOVER
- Max Planck Bristol