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

• 作者: Ganna Petruk Manoj Puthia Jitka Petrlova Firdaus Samsudin Ann-Charlotte Str(o)mdahl Samuel Cerps Lena Uller Sven Kjellstr(o)m Peter J.Bond Artur Schmidtchen
• 来源期刊: 分子细胞生物学报（英文版）
• 年，卷（期）: 2020,（12）
• 所属期刊栏目: Articles
• 页码范围: 916-932
• 页数: 17页
• 语种: 英文
• DOI: 10.1093/jmcb/mjaa067

摘要

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.Here,we define an interaction between SARS-CoV-2 spike(S)protein and LPS,leading to aggravated inflammation in vitro and in vivo.Native gel electrophoresis demonstrated that SARS-CoV-2 S protein binds to LPS.Microscale thermophoresis yielded a KD of～47 nM for the interaction.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.S pro-tein,when combined with low levels of LPS,boosted nuclear factor-kappa B(NF-κB)activation in monocytic THP-1 cells and cyto-kine responses in human blood and peripheral blood mononuclear cells,respectively.The in vitro inflammatory response was fur-ther validated by employing NF-κB reporter mice and in vivo bioimaging.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.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.