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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 LU orcid ; Puthia, Manoj LU ; Petrlova, Jitka LU ; Macary, Paul ; Anand, Ganesh S. ; Bond, Peter J. and Schmidtchen, Artur LU (2022) In Journal of Molecular Cell Biology 14(9). p.1-14
Abstract

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... (More)

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-κB) activation in monocytic THP-1 cells is strongly boosted by S2. Using NF-κB 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.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
COVID-19, hyperinflammation, lipopolysaccharide, SARS-CoV-2, spike protein, TLR4
in
Journal of Molecular Cell Biology
volume
14
issue
9
article number
mjac058
pages
1 - 14
publisher
Oxford University Press
external identifiers
  • pmid:36240490
  • scopus:85140999222
ISSN
1674-2788
DOI
10.1093/jmcb/mjac058
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2022 The Author(s). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.
id
b399a2b0-c877-4fcc-ad69-fb18acb70265
date added to LUP
2025-02-16 09:20:09
date last changed
2025-03-02 10:09:59
@article{b399a2b0-c877-4fcc-ad69-fb18acb70265,
  abstract     = {{<p>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-κB) activation in monocytic THP-1 cells is strongly boosted by S2. Using NF-κB 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.</p>}},
  author       = {{Samsudin, Firdaus and Raghuvamsi, Palur and Petruk, Ganna and Puthia, Manoj and Petrlova, Jitka and Macary, Paul and Anand, Ganesh S. and Bond, Peter J. and Schmidtchen, Artur}},
  issn         = {{1674-2788}},
  keywords     = {{COVID-19; hyperinflammation; lipopolysaccharide; SARS-CoV-2; spike protein; TLR4}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{9}},
  pages        = {{1--14}},
  publisher    = {{Oxford University Press}},
  series       = {{Journal of Molecular Cell Biology}},
  title        = {{SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade}},
  url          = {{http://dx.doi.org/10.1093/jmcb/mjac058}},
  doi          = {{10.1093/jmcb/mjac058}},
  volume       = {{14}},
  year         = {{2022}},
}