SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade
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SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade. / Samsudin, Firdaus; Raghuvamsi, Palur; Petruk, Ganna; Puthia, Manoj; Petrlova, Jitka; MacAry, Paul; Anand, Ganesh S.; Bond, Peter J.; Schmidtchen, Artur.
In: Journal of Molecular Cell Biology, Vol. 14, No. 9, mjac058, 2023, p. 1-14.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade
AU - Samsudin, Firdaus
AU - Raghuvamsi, Palur
AU - Petruk, Ganna
AU - Puthia, Manoj
AU - Petrlova, Jitka
AU - MacAry, Paul
AU - Anand, Ganesh S.
AU - Bond, Peter J.
AU - Schmidtchen, Artur
PY - 2023
Y1 - 2023
N2 - 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-kappa B) activation in monocytic THP-1 cells is strongly boosted by S2. Using NF-kappa B 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.
AB - 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-kappa B) activation in monocytic THP-1 cells is strongly boosted by S2. Using NF-kappa B 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.
KW - COVID-19
KW - SARS-CoV-2
KW - spike protein
KW - lipopolysaccharide
KW - TLR4
KW - hyperinflammation
U2 - 10.1093/jmcb/mjac058
DO - 10.1093/jmcb/mjac058
M3 - Journal article
C2 - 36240490
VL - 14
SP - 1
EP - 14
JO - Journal of Molecular Cell Biology
JF - Journal of Molecular Cell Biology
SN - 1674-2788
IS - 9
M1 - mjac058
ER -
ID: 340096952