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

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>There is a well-known and established link between high lipopolysaccharide (LPS) levels in blood and the metabolic syndrome (MS). MS is a risk factor for developing severe COVID-19 and acute respiratory distress syndrome (ARDS). Here we define an interaction between SARS-CoV-2 Spike (S) protein and LPS and its link to aggravated inflammation in vitro and in vivo. Electrophoresis under native conditions demonstrated that SARS-CoV-2 S protein binds to <jats:italic>Escherichia coli</jats:italic> LPS, forming high molecular weight aggregates. Microscale thermophoresis analysis further defined the interaction, having a K<jats:sub>D</jats:sub> of ~47 nM, similar to the observed affinity between LPS and the human receptor CD14. Moreover, S protein, when combined with low levels of LPS, boosted nuclear factor-kappa B (NF-κB) and cytokine responses in monocytic THP-1 cells and human blood, respectively. In an experimental model of localized inflammation, employing NF-κB reporter mice and in vivo bioimaging, S protein in conjunction with LPS significantly increased the inflammatory response when compared with S protein and LPS alone. Apart from providing information on LPS as a ligand for S protein, our results are of relevance for studies on comorbidities involving bacterial endotoxins, such as the MS, or co-existing acute and chronic infections in COVID-19 patients.</jats:p>

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“…41,42 While LPS's are well-known for their role in triggering gram-negative bacterial sepsis, their role in other acute infections and respiratory diseases is likely broader, and involves complex sequences of cytokine signaling. [43][44][45][46] Nevertheless, as our MR studies showed that LBP and IL10RB protein levels affected COVID-19 outcome with a concordant effect direction, and given the known role of overt inflammation in COVID-19 morbidity, this pathway likely deserves more investigation.…”

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“…Notably, while succinate levels were not found to be increased in the serum of COVID-19 patients, the authors of the study in question hypothesized that succinate levels may have been significantly lowered by the patients’ intense respiratory therapy at the time of blood draw ( Thomas et al, 2020 ). Of further interest is the finding that lipopolysaccharide, which is known to increase succinate levels, has been correlated with more severe COVID-19 outcomes; for example, newer smokers and patients with pneumonia and other lung infections – demographics associated with high lipopolysaccharide levels – are known to be at greater risk of COVID-19 complications and mortalities ( Petruk et al, 2020 ).…”

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“…Lipid A then initiates a signaling cascade resulting in activation of various proinflammatory pathways (predominantly NF- κB) and increases oxidative stress upon binding to TLR4 ( Asehnoune et al, 2004 ; Boutagy et al, 2016 ). Last but not least, Petruk et al in their preprint reported an interconnection between the S-glycoprotein of SARS CoV-2 and LPS, and their link to induction of NF-κB and cytokine responses in monocytes and human blood, as well as significantly increased NF-κB responses in experimental animal models ( Petruk et al, 2020 ). Taking everything previously mentioned into consideration, it is very likely that gut microbiome dysbiosis and endotoxemia represent the additional pathophysiological explanation for increased COVID-19 severity in obesity ( Fig.…”