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SARS-CoV-2: A new mode of virus transmission involving immune cells

Scientists from CNRS, CEA and the UGA confirm in PLOS Pathogens, that the Covid virus can use immune cells to increase its transmission to other cells. The researchers have also shown that it is possible to inhibit this new mode of transmission of the virus by using previously developed glycomimetics. This work is the result of an international collaboration with teams from Spain (Hospital Universitario 12 de Octubre, Madrid) and Italy (Universita degli Studi di Milano).

Published on 20 May 2021
Generally speaking, cells have receptors on their surface, some of which are used only for the attachment of viruses, while others can act as locks that viruses use to gain entry. They have an arsenal of proteins, like a set of keys, that allow them to cross the cell barrier. For example, the S-glycoprotein on the surface of SARS-CoV-2 allows the virus to enter human cells via its interaction with the ACE2 receptor on the surface of infected cells.

Interaction with proteins of the lectin family present on immune cells
Scientists from the Institute of Structural Biology (IBS) in Grenoble (CNRS-CEA-UGA), and their collaborators, discovered that the S protein also interacts with other receptors than ACE2: proteins of the lectin family (DC-SIGN, L-SIGN, MGL and Langerin), present on immune cells. "This interaction involves multi-site recognition of the S protein by exploiting the different surface glycans (sugars) of the S protein," explains Franck Fieschi, professor at Grenoble Alpes University. The S glycoprotein therefore possesses a whole set of keys to enable SARS-CoV-2 to proliferate.

The scientists showed that this interaction did not cause direct infection of cells by SARS-CoV-2. However, of these receptors, DC-SIGN and L-SIGN are able, once they have attached the virus to the cell, to transmit it to permissive cells possessing ACE2.

Uptake of SARS-CoV2 by DC-SIGN and/or L-SIGN receptors promotes transfection of virus-permissive cells (ACE2+). Right-hand diagram: The interaction between DC-SIGN or L-SIGN and the Spike protein involves the recognition of the glycan 'shield' (the sugars coating the Spike protein) by the sugar recognition domains of the lectin receptors.
© Université Grenoble Alpes

Glycomimetic inhibitors
They have also shown that it is possible to inhibit this mode of virus transmission by using glycomimetics, molecules that can mimic the surface sugars of the virus.
These results, already demonstrated on pseudo viruses a few months ago in pre-publication, have now been confirmed by the use of authentic SARS-CoV-2 viruses and on human respiratory cells. The glycomimetic inhibitors developed will thus be able to constitute a first tool to study, in the months to come, the relative importance of this new mode of transmission.

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