biostudies-literaturePetrlova JAlfred Österlunds StiftelseCrafoordska StiftelsenVetenskapsrådetLEO FoundationTorsten Söderbergs StiftelsePetrus och Augusta Hedlunds StiftelseGreta och Johan Kocks stiftelser2566-2575https://www.ebi.ac.uk/biostudies/studies/S-EPMC9538650biostudies-literatureUnknown596(19)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.FEBS lettersSARS-CoV-2 spike protein aggregation is triggered by bacterial lipopolysaccharide.PMC9538650LF-OC-20-0004352017‐023412020‐02016Bond PJSamsudin FPetrlova JSchmidtchen AfalseSARS-CoV-2 spike protein aggregation is triggered by bacterial lipopolysaccharide.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.2022-01-01T00:00:00Z2022 Oct2025-04-04T22:32:45.222Z2025-02-19T03:23:05.587ZS-EPMC95386503605080610.1002/1873-3468.14490