PT  - JOURNAL ARTICLE
AU  - Endika Prieto-Fernández
AU  - Leire Egia-Mendikute
AU  - Laura Vila-Vecilla
AU  - Alexandre Bosch
AU  - Adrián Barreira-Manrique
AU  - So Young Lee
AU  - Ana García-del Río
AU  - Asier Antoñana-Vildosola
AU  - Borja Jiménez-Lasheras
AU  - Leire Moreno-Cugnon
AU  - Jesús Jiménez-Barbero
AU  - Edurne Berra
AU  - June Ereño-Orbea
AU  - Asis Palazon
TI  - Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate
AID  - 10.1101/2021.01.09.426021
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.09.426021
4099  - http://biorxiv.org/content/early/2021/05/17/2021.01.09.426021.short
4100  - http://biorxiv.org/content/early/2021/05/17/2021.01.09.426021.full
AB  - 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-1α-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.Competing Interest StatementThe authors have declared no competing interest.