Abstract 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 K D 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.
【저자키워드】 COVID-19, SARS-CoV-2, Inflammation, Spike protein, metabolic syndrome, lipopolysaccharide, aggregation, 【초록키워드】 severe COVID-19, S protein, Comorbidity, in vitro, Molecular dynamics simulation, Peripheral blood, Protein, mice, Patient, molecular, in vivo, reporter, transmission electron microscopy, Blood, SARS-CoV-2 spike, SARS-CoV-2 S protein, NF-κB, Bacterial, LPS, Interaction, Inflammatory response, Analysis, cytokine response, mononuclear cells, Activation, syndrome, excessive inflammation, dynamic, gel electrophoresis, nuclear, Cell, THP-1, bind, demonstrated, modulated, infection with SARS-CoV-2, Native, scattering, 【제목키워드】 proinflammatory, SARS-CoV-2 spike protein, boost, bacterial lipopolysaccharide, bind,