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

作　　者：Firdaus Samsudin Palur Raghuvamsi Ganna Petruk Manoj Puthia Jitka Petrlova Paul MacAry Ganesh S.Anand Peter J.Bond Artur Schmidtchen 

机构地区：[1]Bioinformatics Institute(BIl),Agency for Science,Technology and Research(A*STAR),Singapore 138671,Singapore [2]Department of Biological Sciences,National University of Singapore,Singapore 117543,Singapore [3]Division of Dermatology and Venereology,Department of Clinical Sciences,Lund University,SE-22184 Lund,Sweden [4]Life Sciences Institute,Centre for Life Sciences,National University of Singapore,Singapore 117546,Singapore [5]Department of Chemistry,The Pennsylvania State University,PA 16801,USA [6]Copenhagen Wound Healing Center,Bispebjerg Hospital,Department of Biomedical Sciences,University of Copenhagen,DK-2400 Copenhagen,Denmark

出　　处：《Journal of Molecular Cell Biology》2022年第9期26-39,共14页分子细胞生物学报（英文版）

基　　金：This work was supported by BIl(A*STAR)core funds;grants FY21_CF_HTPO SEED_ID_BIl_C211418001 funded by A*STAR;the Swedish Research Council(projects 2017-02341 and 2020-02016);Edvard Welanders Stiftelse and Finsenstiftelsen(Hudfonden);the Torsten Soderberg,Crafoord,and Osterlund Foundations,Stiftelsen Lars Hiertas Minne;the Royal Physiographic Society of Lund,and the Swedish Government Funds for Clinical Research(ALF).

摘　　要：Accumulating evidence indicates a potential role for bacterial lipopolysaccharide(LPs)in the overactivation of the immune response during SARS-CoV-2 infection.LPS is recognized by Toll-like receptor 4,mediating proinflammatory effects.We previously reported that LPS directly interacts with SARS-CoV-2 spike(S)protein and enhances proinflammatory activities.Using native gel electrophoresis and hydrogen-deuterium exchange mass spectrometry,we showed that LPS binds to multiple hydrophobic pockets spanning both the S1 and S2 subunits of the S protein.Molecular simulations validated by a microscale thermophoresis binding assay revealed that LPS binds to the S2 pocket with a lower affinity compared to S1,suggesting a role as an intermediate in LPS transfer.Congruently,nuclear factor-kappa B(NF-kB)activation in monocytic THP-1 cells is strongly boosted by S2.Using NF-kB reporter mice followed by bioimaging,a boosting effect was observed for both S1 and S2,with the former potentially facilitated by proteolysis.The Omicron S variant binds to LPS,but with reduced affinity and LPS boosting in vitro and in vivo.Taken together,the data provide a molecular mechanism by which S protein augments LPS-mediated hyperinflammation.

关 键 词：COVID-19 SARS-CoV-2 spike protein LIPOPOLYSACCHARIDE TLR4 hyperinflammation 

分 类 号：R563.1[医药卫生—呼吸系统]