Binding to surface sugars enhances Omicron's cell attachment

A new study from Umeå University reveals how SARS-CoV-2 variants, including Omicron, have adapted to bind more effectively to human pulmonary cells. The stronger binding is explained by an increased and optimised interaction between the virus and heparan sulfate, a long sugar molecule on the cell surface.

“This interaction gives the virus a new attachment point to the cell and may affect the virus's infection, spread and disease symptoms”, says Dario Conca, lead author of the study and postdoctoral fellow at the Department of Clinical Microbiology at Umeå University.

High spread and mild symptoms

Viruses mutate when they replicate in the host, which leads to the emergence of variants that are better adapted to the human host. Like other viruses, SARS-CoV-2 changed during the COVID-19 pandemic and the Omicron variant emerged at the end of 2021. Omicron infected and replicated better in cells high up in the respiratory tract, but less often in tissue further down in the lungs. This may explain why it had very high transmission rate but caused a relatively mild disease.

In addition, viruses need to firmly bind to the host cell before infection, in a similar way as a ship needs to be anchored before the passengers can disembark. This new study shows that SARS-CoV-2 evolved to optimise its binding to the host cell before starting infection. In particular, the increase in binding is dependent on the presence of the sugar molecule heparan sulfate – which is found in abundant amounts on most cell surfaces.

New and more attachment points

Omicron shows a strong and stable interaction with heparan sulfate, which was not present in early variants.

“This indicates that Omicron utilizes heparan sulfate as an extra important attachment point, which in turn provides access to new and numerous anchoring sites in the upper respiratory tract”, says Marta Bally, associate professor at the Department of Clinical Microbiology at Umeå University.

For the early variants of the virus, heparan sulfate acted more like a shield, reducing interactions at the cell surface. In this case, virus-sugar molecule bonds promoted virus mobility rather than attachment, with a possible easier spread in the lungs.

Advanced biophysical methods

In the study, the researchers studied binding of single virus particles to cell membrane isolates, which closely resemble the cellular surface a virus faces in the body.

They used advanced biophysical methods, including high-resolution microscopy and atomic force microscopy, to address the virus behaviour at the cell surface and determine the importance of single surface molecules, like heparan sulfate, in viral infection.

Viral infections are complex

The study highlights the complexity of the molecular interactions that characterize viral infections and how these interactions can affect the spread and severity of the virus.

“In this case, the ability of the virus to exploit multiple, more common targets appears to have been one of the driving forces for SARS-CoV-2 evolution during the pandemic”, says Dario Conca.

“Although this study is only a first step in this direction, we believe that unveiling the link between molecular interactions and the resulting disease is fundamental to understand and ultimately fight viral infections,” says Marta Bally.

The results have been published in the journal Analytical Chemistry.

About the scientific article:
Conca, D. et al: Variant-Specific Interactions at the Plasma Membrane: Heparan Sulfate’s Impact on SARS-CoV-2 Binding Kinetics. Analytical Chemistry. 2025, 97, 8- https://doi.org/10.1021/acs.analchem.4c04283

For more information, please contact:
Dario Conca, Department of Clinical Microbiology, Umeå University
Mobile: 079-334 78 79
Email: dario.conca@umu.se

Marta Bally, Department of Clinical Microbiology, Umeå University
Phone: 090 786 89 06
Email: marta.bally@umu.se

Photos
Caption 1: Dario Conca, postdoctoral fellow at the Department of Clinical Microbiology at Umeå University (pic 5552)
Caption 2: The researchers' findings are well aligned with Omicron’s tendency to cause milder disease symptoms, compared to previous variants of the virus that more often targeted deeper parts of the respiratory system. (pic 5560)
Caption 3: The focus in Marta Bally’s research group is molecular interactions during viral entry. (pic 5555)