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SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade
Firdaus Samsudin1,† , Palur Raghuvamsi1,2,† , Ganna Petruk3,† , Manoj Puthi3,† , Jitka Petrlova3 , Paul MacAry4 , Ganesh S. Anand2,5 , Peter J. Bond1,2,* , Artur Schmidtchen3,6,*
1Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore
2Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
3Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184 Lund, Sweden
4Life Sciences Institute, Centre for Life Sciences, National University of Singapore, Singapore 117546, Singapore
5Department of Chemistry, The Pennsylvania State University, PA 16801, USA
6Copenhagen Wound Healing Center, Bispebjerg Hospital, Department of Biomedical Sciences, University of Copenhagen, DK-2400 Copenhagen, Denmark
These authors contributed equally to this work.
*Correspondence to:Peter J. Bond , Artur Schmidtchen ,
J Mol Cell Biol, Volume 14, Issue 9, September 2022, mjac058,
Keyword: COVID-19, SARS-CoV-2, spike protein, lipopolysaccharide, TLR4, hyperinflammation

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-κB) activation in monocytic THP-1 cells is strongly boosted by S2. Using NF-κB 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.