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.
Keywords:
ACE2; SARS-CoV-2; heparan sulfate; hypoxia; syndecan-1.
MeSH terms
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Angiotensin-Converting Enzyme 2 / genetics
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Angiotensin-Converting Enzyme 2 / metabolism*
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Animals
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Cell Hypoxia / physiology*
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Chlorocebus aethiops
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Gene Expression Regulation / drug effects
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Heparitin Sulfate / genetics
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Heparitin Sulfate / metabolism*
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Humans
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Neuropilin-1 / genetics
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Neuropilin-1 / metabolism*
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SARS-CoV-2 / physiology
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Spike Glycoprotein, Coronavirus / chemistry
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Spike Glycoprotein, Coronavirus / physiology*
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Syndecan-1 / genetics
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Syndecan-1 / metabolism*
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Vero Cells
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Virus Attachment / drug effects
Substances
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SDC1 protein, human
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Spike Glycoprotein, Coronavirus
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Syndecan-1
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spike protein, SARS-CoV-2
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Neuropilin-1
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Heparitin Sulfate
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ACE2 protein, human
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Angiotensin-Converting Enzyme 2
Grants and funding
This research was supported by the SPRI I+D COVID-19 fund (Basque Government, bG-COVID-19), the European Research Council (ERC) (grant numbers: ERC-2018-StG 804236-NEXTGEN-IO to A.P and ERC-2017-AdG 788143-RECGLYCANMR to J.J-B.), the Severo Ochoa Excellence Accreditation from MCIU (SEV-2016-0644) and the FERO Foundation. Personal fellowships: E.P. (Juan de la Cierva-Formación, FJC2018-035449-I), L.V. (Juan de la Cierva-Formación, FJCI-2017-34099), A.B. (AECC Bizkaia Scientific Foundation, PRDVZ19003BOSC), A.G. (Programa Bikaintek from the Basque Government, 48-AF-W1-2019-00012), A.A (La Caixa Inphinit, LCF/BQ/DR20/11790022), B.J. (Basque Government, PRE_2019_1_0320), L.M. (Juan de la Cierva-Formación, FJC2019-039983-I), E.B. (MINECO, BFU2016-76872-R; Excellence Networks, SAF2017-90794-REDT) and A.P. (Ramón y Cajal, RYC2018-024183-I; Proyectos I+D+I, PID2019-107956RA-I00; and Ikerbasque Research Associate).