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

Firdaus Samsudin, Palur Raghuvamsi, Ganna Petruk, Manoj Puthia, Jitka Petrlova, Paul MacAry, Ganesh S. Anand, View ORCID ProfileArtur Schmidtchen, View ORCID ProfilePeter J. Bond
doi: https://doi.org/10.1101/2021.10.29.466401
Firdaus Samsudin
1Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore
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Palur Raghuvamsi
1Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore
2Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
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Ganna Petruk
3Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184 Lund, Sweden
4Xinnate AB, Medicon Village, SE-22381 Lund, Sweden
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Manoj Puthia
3Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184 Lund, Sweden
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Jitka Petrlova
3Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184 Lund, Sweden
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Paul MacAry
5Life Sciences Institute, Centre for Life Sciences, National University of Singapore, 28 Medical Drive, Singapore 117546, Singapore
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Ganesh S. Anand
2Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
6Department of Chemistry, The Pennsylvania State University, 104 Chemistry Building, University Park, PA, USA
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Artur Schmidtchen
3Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, SE-22184 Lund, Sweden
7Copenhagen Wound Healing Center, Bispebjerg Hospital, Department of Biomedical Sciences, University of Copenhagen, DK-2400 Copenhagen, Denmark
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  • ORCID record for Artur Schmidtchen
  • For correspondence: peterjb@bii.a-star.edu.sg artur.schmidtchen@med.lu.se
Peter J. Bond
1Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore 138671, Singapore
2Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
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  • ORCID record for Peter J. Bond
  • For correspondence: peterjb@bii.a-star.edu.sg artur.schmidtchen@med.lu.se
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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 recognised by Toll-like receptor 4 (TLR4) in innate immunity. Here, we showed that LPS binds to multiple hydrophobic pockets spanning both the S1 and S2 subunits of the SARS-CoV-2 spike (S) protein. LPS binds to the S2 pocket with a lower affinity compared to S1, suggesting its possible role as an intermediate in the TLR4 cascade. Congruently, nuclear factor-kappa B (NF-κB) activation in vitro is strongly boosted by S2. In vivo, however, a boosting effect is observed for both S1 and S2, with the former potentially facilitated by proteolysis. Collectively, our study suggests the S protein may act as a delivery system for LPS in host innate immune pathways. The LPS binding pockets are highly conserved across different SARS-CoV-2 variants and therefore represent potential therapeutic targets.

Competing Interest Statement

A.S. is a founder and shareholder of in2cure AB, a company developing therapies based on host defence peptides. A patent application related to the present work, with A.S., G.P. and M.P. listed as inventors, has been filed.

Footnotes

  • ↵# Considered as joint first author

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 06, 2021.
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SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade
Firdaus Samsudin, Palur Raghuvamsi, Ganna Petruk, Manoj Puthia, Jitka Petrlova, Paul MacAry, Ganesh S. Anand, Artur Schmidtchen, Peter J. Bond
bioRxiv 2021.10.29.466401; doi: https://doi.org/10.1101/2021.10.29.466401
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SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade
Firdaus Samsudin, Palur Raghuvamsi, Ganna Petruk, Manoj Puthia, Jitka Petrlova, Paul MacAry, Ganesh S. Anand, Artur Schmidtchen, Peter J. Bond
bioRxiv 2021.10.29.466401; doi: https://doi.org/10.1101/2021.10.29.466401

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