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.
Highlights
SARS-CoV-2 infection is a major global public health concern with incompletely understood pathogenesis
minimal virions (MiniVs) functionality and binding specificity towards angiotensin-converting enzyme 2 (ACE2) receptors were verified by quartz crystal microbalance with dissipation monitoring (QCM-D)
We found that MiniVs bind to ACE2 receptors with neglectable non-specific attachment to lipid membranes
Summary
SARS-CoV-2 infection is a major global public health concern with incompletely understood pathogenesis. Molecular mechanisms that modulate S open-to-closed equilibrium and their implications for SARS-CoV-2 infection and immune evasion remain poorly understood Exogenous control of this equilibrium, could greatly benefit COVID-19 therapy development and promote prospective pandemic prevention. A major advantage of our synthetic virions over live SARS-CoV-2 and pseudoviruses is the ability to test S binding exercising precise control over the FFAloading in the FABP in a safety level 1 laboratory environment. This enables a systematic assessment of FABP-based S functional regulation of SARS-CoV-2 infectivity and IgG immunogenicity
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