Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.

中文翻译：

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转铁蛋白受体是SARS-CoV-2进入的另一种受体

血管紧张素转换酶2（ACE2）已被建议作为严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）进入的受体，导致2019年冠状病毒疾病（COVID-19）。但是，没有ACE2抑制剂对COVID-19患者显示出明确的受益者，而存在另一种SARS-CoV-2进入受体。在这里，我们显示ACE2敲除并未完全阻止病毒进入，而TfR与病毒Spike蛋白直接相互作用以介导病毒进入，SARS-CoV-2可以感染过度表达的人源化转铁蛋白受体（TfR）而没有人源化ACE2的小鼠。在膜和细胞质中均发现了TfR-病毒共定位，这表明SARS-CoV-2通过TfR进行了转运，铁转运受体在细胞膜和细胞质之间穿梭。干扰TfR-Spike相互作用会阻止病毒进入，从而发挥重要的抗病毒作用。抗TfR抗体（EC50 16.6 nM）在小鼠模型中显示出有希望的抗病毒作用。总体而言，该报告表明TfR是SARS-CoV-2进入的另一种受体，也是有希望的抗COVID-19靶标。