lipid-a and Cytokine-Release-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.

Topics: Animals; Binding Sites; COVID-19; Cytokine Release Syndrome; Disease Models, Animal; Gram-Negative Bacterial Infections; Humans; In Vitro Techniques; Inflammation; Lipid A; Lipopolysaccharides; Mice; Mice, Inbred BALB C; Mice, Transgenic; Models, Immunological; Models, Molecular; Molecular Docking Simulation; Protein Binding; Protein Interaction Domains and Motifs; Respiratory Distress Syndrome; Risk Factors; SARS-CoV-2; Spike Glycoprotein, Coronavirus