Hypoxia Reduces Cell Attachment of SARS-CoV-2 Spike Protein by Modulating the Expression of ACE2, Neuropilin-1, Syndecan-1 and Cellular Heparan Sulfate
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Date
2021-06-06Author
Prieto Fernández, Endika
Egia Mendikute, Leire
Vila Vecilla, Laura
Bosch, Alexandre
Barreira Manrique, Adrián
Lee, So Young
García del Río, Ana
Antoñana Vildosola, Asier
Jiménez Lasheras, Borja
Moreno Cugnon, Leire
Berra Ramírez, Miren Edurne
Ereño Orbea, June
Palazón, Asís
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Emerging Microbes And Infections 10(1) : 1065-1076 (2021)
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-1αdependent 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 signalling pathway might
offer therapeutic opportunities for the treatment of COVID-19.