SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade
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Accumulating evidence indicates a potential role for bacterial lipopolysaccharide (LPS) in the overactivation of the immune response during SARS-CoV-2 infection. LPS is recognized by Toll-like receptor 4, mediating proinflammatory effects. We previously reported that LPS directly interacts with SARS-CoV-2 spike (S) protein and enhances proinflammatory activities. Using native gel electrophoresis and hydrogen-deuterium exchange mass spectrometry, we showed that LPS binds to multiple hydrophobic pockets spanning both the S1 and S2 subunits of the S protein. Molecular simulations validated by a microscale thermophoresis binding assay revealed that LPS binds to the S2 pocket with a lower affinity compared to S1, suggesting a role as an intermediate in LPS transfer. Congruently, nuclear factor-kappa B (NF-kappa B) activation in monocytic THP-1 cells is strongly boosted by S2. Using NF-kappa B reporter mice followed by bioimaging, a boosting effect was observed for both S1 and S2, with the former potentially facilitated by proteolysis. The Omicron S variant binds to LPS, but with reduced affinity and LPS boosting in vitro and in vivo. Taken together, the data provide a molecular mechanism by which S protein augments LPS-mediated hyperinflammation.
Original language | English |
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Article number | mjac058 |
Journal | Journal of Molecular Cell Biology |
Volume | 14 |
Issue number | 9 |
Pages (from-to) | 1-14 |
ISSN | 1674-2788 |
DOIs | |
Publication status | Published - 2023 |
- COVID-19, SARS-CoV-2, spike protein, lipopolysaccharide, TLR4, hyperinflammation
Research areas
ID: 340096952