Engineering Laboratory of Peptides of Chinese Academy of Sciences, Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology-Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), and Sino-African Joint Research Center, New Cornerstone Science Laboratory, Kunming Institute of Zoology, The Chinese Academy of Sciences, Kunming 650201, China.
Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China.
Proc Natl Acad Sci U S A. 2024 Mar 5;121(10):e2317026121. doi: 10.1073/pnas.2317026121. Epub 2024 Feb 26.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been detected in almost all organs of coronavirus disease-19 patients, although some organs do not express angiotensin-converting enzyme-2 (ACE2), a known receptor of SARS-CoV-2, implying the presence of alternative receptors and/or co-receptors. Here, we show that the ubiquitously distributed human transferrin receptor (TfR), which binds to diferric transferrin to traffic between membrane and endosome for the iron delivery cycle, can ACE2-independently mediate SARS-CoV-2 infection. Human, not mouse TfR, interacts with Spike protein with a high affinity (K ~2.95 nM) to mediate SARS-CoV-2 endocytosis. TfR knock-down (TfR-deficiency is lethal) and overexpression inhibit and promote SARS-CoV-2 infection, respectively. Humanized TfR expression enables SARS-CoV-2 infection in baby hamster kidney cells and C57 mice, which are known to be insusceptible to the virus infection. Soluble TfR, Tf, designed peptides blocking TfR-Spike interaction and anti-TfR antibody show significant anti-COVID-19 effects in cell and monkey models. Collectively, this report indicates that TfR is a receptor/co-receptor of SARS-CoV-2 mediating SARS-CoV-2 entry and infectivity by likely using the TfR trafficking pathway.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）已在大多数 COVID-19 患者的器官中检测到，尽管一些器官不表达血管紧张素转换酶 2（ACE2），这是 SARS-CoV-2 的已知受体，这表明存在替代受体和/或共受体。在这里，我们表明普遍分布的人转铁蛋白受体（TfR）可以 ACE2 独立地介导 SARS-CoV-2 感染。与人 TfR 结合，二价铁转铁蛋白在膜和内体之间运输以完成铁输送循环，与 Spike 蛋白具有高亲和力（K ~2.95 nM）相互作用以介导 SARS-CoV-2 内吞作用。TfR 敲低（TfR 缺陷是致命的）和过表达分别抑制和促进 SARS-CoV-2 感染。人源化 TfR 表达使 SARS-CoV-2 能够感染已知对病毒感染不敏感的仓鼠肾细胞和 C57 小鼠。可溶性 TfR、Tf、设计用于阻断 TfR-Spike 相互作用的肽以及抗 TfR 抗体在细胞和猴子模型中均显示出显著的抗 COVID-19 作用。总的来说，该报告表明 TfR 是 SARS-CoV-2 的受体/共受体，通过可能使用 TfR 转运途径来介导 SARS-CoV-2 的进入和感染性。
