SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Bacterial lipopolysaccharide (LPS) and SARS-CoV-2 infection can independently trigger immune overactivation.
• LPS activates the immune system via Toll-like receptor 4, leading to proinflammatory effects.
• Previous studies suggest a direct interaction between LPS and the SARS-CoV-2 spike (S) protein.

Purpose of the Study:

• To elucidate the molecular mechanism by which the SARS-CoV-2 S protein enhances LPS-mediated hyperinflammation.
• To investigate the binding sites and affinity of LPS to the S protein.
• To assess the impact of S protein-LPS interaction on immune cell activation.

Main Methods:

• Native gel electrophoresis and hydrogen-deuterium exchange mass spectrometry to identify LPS binding sites on the S protein.
• Molecular simulations and microscale thermophoresis assay to quantify binding affinity.
• NF-κB reporter assays in THP-1 cells and NF-κB reporter mice to evaluate immune activation.

Main Results:

• LPS binds to hydrophobic pockets in both S1 and S2 subunits of the SARS-CoV-2 S protein.
• The S2 subunit plays a significant role in boosting NF-κB activation, potentially acting as an LPS transfer intermediate.
• The Omicron variant shows reduced affinity for LPS and diminished boosting effects.
• In vivo studies confirmed the boosting effect of S protein subunits on NF-κB activation.

Conclusions:

• The SARS-CoV-2 S protein directly interacts with LPS, providing a molecular basis for augmented immune responses.
• This interaction amplifies LPS-mediated inflammation, contributing to hyperinflammation during SARS-CoV-2 infection.
• Understanding this mechanism offers insights into potential therapeutic strategies targeting viral-bacterial co-infections.