SARS-CoV-2 spike protein aggregation is triggered by bacterial lipopolysaccharide

FEBS Lett. 2022 Oct;596(19):2566-2575. doi: 10.1002/1873-3468.14490. Epub 2022 Sep 11.


SARS-CoV-2 spike (S) protein is crucial for virus invasion in COVID-19. Here, we showed that lipopolysaccharide (LPS) can trigger S protein aggregation at high doses of LPS and S protein. We demonstrated the formation of S protein aggregates by microscopy analyses, aggregation and gel shift assays. LPS at high levels boosts the formation of S protein aggregates as detected by amytracker and thioflavin T dyes that specifically bind to aggregating proteins. We validated the role of LPS by blocking the formation of aggregates by the endotoxin-scavenging thrombin-derived peptide TCP-25. Aggregation-prone sequences in S protein are predicted to be nearby LPS binding sites, while molecular simulations showed stable formation of S protein-LPS higher-order oligomers. Collectively, our results provide evidence of LPS-induced S protein aggregation.

Keywords: COVID-19; endotoxins; inflammation; lipopolysaccharide; protein-aggregation; spike protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19*
  • Coloring Agents
  • Humans
  • Lipopolysaccharides / metabolism
  • Peptides / metabolism
  • Protein Aggregates
  • Protein Binding
  • SARS-CoV-2
  • Spike Glycoprotein, Coronavirus* / chemistry
  • Thrombin / metabolism


  • Coloring Agents
  • Lipopolysaccharides
  • Peptides
  • Protein Aggregates
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Thrombin