In brief

Bacterial lipopolysaccharides bind to several sites on the SARS-CoV-2 spike protein, initiating a cytokine storm seen in some severe COVID-19 cases.


Catching a COVID co-conspirator

30 May 2023

Researchers identify an unexpected synergy between bacterial and viral molecules that causes severe inflammation in some patients with COVID-19.

During our evolution, humans have forged a strong symbiotic relationship with many species of bacteria, such as those constituting our gut microbiota. The digestive tract gives the community of microorganisms a place to call home, while they help us with digestion, metabolism and immune functions.

However, if bacterial components, such as lipopolysaccharide (LPS), leak out of the gut and into the bloodstream, pro-inflammatory cytokine production may surge—a problem often seen in patients with metabolic syndrome. Viruses can then exacerbate this underlying bacterial infection. “There has been accumulating clinical evidence linking LPS with severe COVID-19 cases,” said Peter Bond, a Senior Principal Investigator at A*STAR’s Bioinformatics Institute (BII).

Prior studies by Bond’s team revealed that LPS latches onto SARS-CoV-2’s spike (S) protein in serious COVID-19 cases, which could explain the exaggerated immune response that leads to acute respiratory distress syndrome (ARDS) and sepsis.

In their follow-up study, Bond collaborated with researchers from Lund University, Pennsylvania State University and the National University of Singapore to investigate the LPS-spike protein interaction in molecular detail.

The scientists deployed a suite of computational modelling and protein binding assays and discovered that LPS clicked into three distinct grooves on the S1 and S2 subunits of the S protein. This unlikely duo acts like an accelerant, sending the innate immune system’s protective mechanisms into overdrive.

According to Bond, interactions between viruses and bacteria aren’t so unusual and they often support viral life cycles. Interestingly, the team found that the S protein of the Omicron variant doesn’t bind to LPS as strongly as earlier variants. This may partially explain why Omicron variants usually cause milder symptoms in patients.

Bond said that the newly discovered LPS binding sites on the S protein are attractive drug targets. “In principle, blocking these sites could inhibit S protein-LPS interactions and subsequent transfer to innate immune receptors,” explained Bond. “This would dampen the boosting effect of LPS-mediated hyperinflammation, which in turn, could prevent severe complications like sepsis.”

Bond’s team is currently working towards identifying potential mutations in the S protein that may block LPS binding and investigating the dynamics between LPS-spike complexes and the immune receptors.

The A*STAR-affiliated researchers contributing to this research are from the Bioinformatics Institute (BII).

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Samsudin, F., Raghuvamsi, P., Petruk, G., Puthia, M., Petrlova, J., et. al. SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade. Journal of Molecular Cell Biology 14 (9), 1-14 (2022) | article

About the Researchers

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Peter J. Bond

Senior Principal Investigator

Bioinformatics Institute (BII)
Peter J. Bond is a Senior Principal Investigator at the Multiscale Simulation, Modelling and Design (MSMD) group at A*STAR’s Bioinformatics Institute. His group develops computational models to resolve the dynamics of biomolecules over multiple time and length scales, focusing particularly on mechanisms of infectious disease, the host immune response to bacterial and viral pathogens and therapeutic intervention strategies.
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Firdaus Samsudin

Senior Postdoctoral Research Fellow

Bioinformatics Institute (BII)
Firdaus Samsudin is a Senior Postdoctoral Research Fellow with the Multiscale Simulation, Modelling and Design (MSMD) group at A*STAR’s Bioinformatics Institute (BII). He graduated with a DPhil in Biochemistry from the University of Oxford. His research interests include understanding the dynamics of large biomolecular complexes using multiscale modelling and simulation towards developing novel therapeutic avenues, exemplified by his work on IgM antibody isotype and the SARS-CoV-2 spike glycoprotein. Samsudin was awarded the 2019 AME YIRG grant for his project entitled “Engineering IgM Antibodies Through Multiscale Modelling and Simulations for Cancer Therapeutics and Detection”.

This article was made for A*STAR Research by Wildtype Media Group