Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2 and heparan sulfate

Prieto-Fernandez, E.; Egia-Mendikute, L.; Vila-Vecilla, L.; Lee, S. Y.; Bosch, A.; Barreira-Manrique, A.; Garcia del Rio, A.; Antonana-Vildosola, A.; Jimenez-Lasheras, B.; Palazon, A.

doi:10.1101/2021.01.09.426021

bioRxiv · 10.1101/2021.01.09.426021

Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2 and heparan sulfate

Prieto-Fernandez, E.·Egia-Mendikute, L.·Vila-Vecilla, L.·Lee, S. Y.·Bosch, A.·Barreira-Manrique, A.·Garcia del Rio, A.·Antonana-Vildosola, A.·Jimenez-Lasheras, B.·Palazon, A.

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Abstract

A main clinical parameter of COVID-19 pathophysiology is hypoxia. Here we show that hypoxia decreases the attachment of the receptor binding domain (RBD) and the S1 subunit (S1) of the spike protein of SARS-CoV-2 to epithelial cells. In Vero E6 cells, hypoxia reduces the protein levels of ACE2 and neuropilin-1 (NRP1), which might in part explain the observed reduction of the infection rate. In addition, hypoxia inhibits the binding of the spike to NCI-H460 human lung epithelial cells by decreasing the cell surface levels of heparan sulfate (HS), a known attachment receptor of SARS-CoV-2. This interaction is also reduced by lactoferrin, a glycoprotein that blocks HS moieties on the cell surface. The expression of syndecan-1, an HS-containing proteoglycan expressed in lung, is inhibited by hypoxia on a HIF-1-dependent manner. Hypoxia or deletion of syndecan-1 results in reduced binding of the RBD to host cells. Our study indicates that hypoxia acts to prevent SARS-CoV-2 infection, suggesting that the hypoxia signaling pathway might offer therapeutic opportunities for the treatment of COVID-19.

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Prieto-Fernandez, E., Egia-Mendikute, L., Vila-Vecilla, L., Lee, S. Y., Bosch, A., Barreira-Manrique, A., Garcia del Rio, A., Antonana-Vildosola, A., Jimenez-Lasheras, B., Palazon, A.. 2021-01-11. Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2 and heparan sulfate. https://doi.org/10.1101/2021.01.09.426021

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