During ARDS, activation of toll-like receptors (TLR), such as TLR4 via lipopolysaccharide (LPS) stimulation, induces an initial systemic proinflammatory phase characterized by a massive release of cytokines, acute phase proteins, and reactive oxygen species ( Rittirsch et al., 2008 van der Poll and Opal, 2008). Increased cytokine and chemokine production in response to virus infection has been the focus of several recent investigations, and patient morbidity and mortality are mainly caused by the severe systemic inflammation and acute respiratory distress syndrome (ARDS) affecting these patients ( Hariri and Hardin, 2020 Whyte et al., 2020), although differences in ARDS disease phenotypes are noticed ( Li and Ma, 2020).ĪRDS is a general systemic inflammatory reaction common for many disease states, such as pneumonia, severe infection, sepsis, burns, and severe trauma. COVID-19 disease is associated with a major inflammatory component. S protein is the most important surface protein of coronavirus including SARS-CoV-2, which can mediate the entrance to human respiratory epithelial cells by interacting with the cell surface receptor angiotensin-converting enzyme 2 ( Wan et al., 2020). 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.Ĭoronaviruses are a group of enveloped positive-stranded RNA viruses that consist of four structural proteins including spike (S) glycoprotein (here denoted S protein), envelope (E) protein, membrane (M) protein, and nucleocapsid (N) protein ( Felsenstein et al., 2020). 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. The in vitro inflammatory response was further validated by employing NF-κB reporter mice and in vivo bioimaging. 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. 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. Microscale thermophoresis yielded a K D of ∼47 nM for the interaction. Native gel electrophoresis demonstrated that SARS-CoV-2 S protein binds to LPS. Here, we define an interaction between SARS-CoV-2 spike (S) protein and LPS, leading to aggravated inflammation in vitro and in vivo. 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.
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