Abstract
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-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 signalling pathway might offer therapeutic opportunities for the treatment of COVID-19.
Highlights
By mid-May of 2021, SARS-CoV-2 has infected over 160 million people and caused >3.3 million deaths
In order to understand if hypoxia could affect the cellular binding capacity of the SARS-CoV-2 spike protein, we subjected Vero E6 cells or human lung epithelial cells (NCI-H460) to different oxygen concentrations (21% O2 or 1% O2) and measured the binding ability of the receptor-binding domain (RBD) and the S1 subunit (S1) of the spike protein to the surface of these cells in vitro
We explored if hypoxia modulates angiotensin-converting enzyme 2 (ACE2) expression on Vero E6 cells
Summary
By mid-May of 2021, SARS-CoV-2 has infected over 160 million people and caused >3.3 million deaths. The spike protein of SARS-CoV-2 interacts with the angiotensin-converting enzyme 2 (ACE2), a keyreceptor widely expressed on the respiratory tract, through the receptor-binding domain (RBD) [3,4,5]. Other factors such as neuropilin-1 (NRP1) [6,7] and the transmembrane protease serine 2 (TMPRSS2) [8] contribute to the entry of SARS-CoV-2 into host cells. The interaction between the spike and HS can be efficiently blocked by lactoferrin [11]
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