SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity

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 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-k B)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-kB 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.