< Previous         Next >  
SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity
Ganna Petruk1,† , Manoj Puthia1,† , Jitka Petrlova1 , Firdaus Samsudin2 , Ann-Charlotte Stro¨mdahl1 , Samuel Cerps3 , Lena Uller3 , Sven Kjellstro¨m4 , Peter J. Bond2,5 , Artur Schmidtchen1,6,7,*
1Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184 Lund, Sweden
2Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore
3Unit of Respiratory Immunopharmacology, Department of Experimental Medicine, Lund University, SE-22184 Lund, Sweden
4Division of Mass Spectrometry, Department of Clinical Sciences, Lund University, SE-22184 Lund, Sweden
5Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
6Copenhagen Wound Healing Center, Bispebjerg Hospital, Department of Biomedical Sciences, University of Copenhagen, DK-2400 Copenhagen, Denmark
7Dermatology, Ska˚ne University Hospital, SE-22185 Lund, Sweden
These authors contributed equally to this work.
*Correspondence to:Artur Schmidtchen ,
J Mol Cell Biol, Volume 12, Issue 12, December 2020, 916-932,
Keyword: COVID-19, SARS-CoV-2, spike protein, lipopolysaccharide, inflammation, aggregation, metabolic syndrome

There is a link between high lipopolysaccharide (LPS) levels in the blood and the metabolic syndrome, and metabolic syndrome predisposes patients to severe COVID-19. Here, we define an interaction between SARS-CoV-2 spike (S) protein and LPS, leading to aggravated inflammation in vitro and in vivo. Native gel electrophoresis demonstrated that SARS-CoV-2 S protein binds to LPS. Microscale thermophoresis yielded a KD of ∼47 nM for the interaction. Computational modeling and all-atom molecular dynamics simulations further substantiated the experimental results, identifying a main LPS-binding site in SARS-CoV-2 S protein. S protein, when combined with low levels of LPS, boosted nuclear factor-kappa B (NF-κB) activation in monocytic THP-1 cells and cytokine responses in human blood and peripheral blood mononuclear cells, respectively. The in vitro inflammatory response was further validated by employing NF-κB reporter mice and in vivo bioimaging. Dynamic light scattering, transmission electron microscopy, and LPS-FITC analyses demonstrated that S protein modulated the aggregation state of LPS, providing a molecular explanation for the observed boosting effect. Taken together, our results provide an interesting molecular link between excessive inflammation during infection with SARS-CoV-2 and comorbidities involving increased levels of bacterial endotoxins.