While getting COVID-19 may already be daunting, the situation is even more complicated for infected individuals with pre-existing conditions. Case in point: COVID-19 patients with metabolic syndrome—a set of disorders including insulin resistance, obesity and hypertension—are more likely to take a turn for the worse and develop hyperinflammation. Still, scientists remain stumped by how exactly metabolic syndrome can aggravate SARS-CoV-2 infection.
New research suggests the answer may lie in bacterial molecules called lipopolysaccharides (LPS). Found in the membranes of Gram-negative bacteria, LPS can sometimes escape the gut and enter the bloodstream—with serious consequences. In acute respiratory distress syndrome—a common manifestation of severe COVID-19—LPS can activate immune cells and induce a massive cytokine storm. Intriguingly, elevated LPS levels in the blood are also a hallmark of metabolic syndrome, hinting at a connection to the two illnesses.
Seeking to tease out the relationship between LPS and SARS-CoV-2, researchers led by Peter Bond, a Senior Principal Investigator at A*STAR’s Bioinformatics Institute (BII), joined forces with long-time collaborator Artur Schmidtchen of Lund University, Sweden. While Schmidtchen’s group focused on in vitro and in vivo experiments, Bond and BII Research Fellow Firdaus Samsudin used computational modeling to identify potential binding sites between LPS and SARS-CoV-2.
To confirm an interaction between LPS and the virus, the research team performed native gel electrophoresis to show that the virus’ spike protein became heavier with increasing doses of LPS.
Computational analysis and all-atom molecular dynamic simulations performed by Bond and Samsudin not only confirmed this binding but also identified a potential site of interaction. Their models showed that LPS most likely slots into a groove right beside the cleavage site linking the two subunits of the spike protein. Interestingly, LPS’ interaction with the spike protein resembles the way it binds to and activates certain host immune cell receptors like CD14 and TLR4.
True enough, the team found that in cell-cultures and mouse models, the binding between LPS and the spike protein activated the transcription factor NF-κB to elicit a strong and prolonged inflammatory response. This response was much more pronounced than when induced by LPS or the spike protein alone—indicating synergy between the two molecules.
“One potential mechanism is that the binding [of LPS and the spike protein] increases the number of free LPS molecules in the blood that can bind to CD14,” explained Bond. “This can potentially trigger the cytokine storm observed in severe COVID-19 patients, and may thus be a target for drugs that seek to prevent severe symptoms.” Testing for raised LPS levels could therefore also help to identify patients with a higher risk of developing severe COVID-19, he concluded.
The A*STAR-affiliated researchers contributing to this research are from the Bioinformatics Institute (BII).