Human transferrin receptor can mediate SARS-CoV-2 infection

• Published in: Proceedings of the National Academy of Sciences - PNAS 2024-03, Vol.121 (10), p.e2317026121-e2317026121
• Main Authors: Liao, Zhiyi, Wang, Chaoming, Tang, Xiaopeng, Yang, Mengli, Duan, Zilei, Liu, Lei, Lu, Shuaiyao, Ma, Lei, Cheng, Ruomei, Wang, Gan, Liu, Hongqi, Yang, Shuo, Xu, Jingwen, Tadese, Dawit Adisu, Mwangi, James, Kamau, Peter Muiruri, Zhang, Zhiye, Yang, Lian, Liao, Guoyang, Zhao, Xudong, Peng, Xiaozhong, Lai, Ren
• Format: Article
• Language: English
• Subjects: ACE2; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - genetics; Angiotensin-Converting Enzyme 2 - metabolism; Animals; Antibodies; Biological Sciences; Cell culture; Coronaviruses; COVID-19; Endocytosis; Endosomes; Humans; Infections; Infectivity; Membrane trafficking; Mice; Organs; Peptides; Peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - metabolism; Protein Binding; Protein transport; Receptors; Receptors, Transferrin - genetics; Receptors, Transferrin - metabolism; Respiratory diseases; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Transferrin; Transferrins; Viral diseases
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2317026121

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.