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.

中文翻译：

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缺氧通过调节ACE2，neuropilin-1，syndecan-1和细胞硫酸乙酰肝素的表达来减少SARS-CoV-2穗蛋白的细胞附着

COVID-19病理生理学的主要临床参数是缺氧。在这里，我们表明缺氧减少了SARS-CoV-2突突蛋白的受体结合域（RBD）和S1亚基（S1）对上皮细胞的附着。在Vero E6细胞中，缺氧会降低ACE2和Neuropilin-1（NRP1）的蛋白水平，这可能部分解释了观察到的感染率降低。另外，低氧通过降低硫酸盐乙酰肝素（HS）（一种已知的SARS-CoV-2附着受体）的细胞表面水平，抑制刺突与NCI-H460人肺上皮细胞的结合。乳铁蛋白也可以减少这种相互作用，乳铁蛋白是一种阻断细胞表面HS部分的糖蛋白。缺氧以HIF-1α依赖性方式抑制syndecan-1（一种在肺中表达的含HS的蛋白聚糖）的表达。缺氧或syndecan-1缺失导致RBD与宿主细胞的结合减少。我们的研究表明，低氧可预防SARS-CoV-2感染，提示低氧信号通路可能为COVID-19的治疗提供治疗机会。