Human transferrin receptor can mediate SARS-CoV-2 infection

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 (KD ~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.

Keywords: SARS-CoV-2; alternative receptors; interaction; spike; transferrin receptor.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • COVID-19*
  • Humans
  • Mice
  • Peptidyl-Dipeptidase A / metabolism
  • Protein Binding
  • Receptors, Transferrin / genetics
  • Receptors, Transferrin / metabolism
  • SARS-CoV-2 / metabolism
  • Spike Glycoprotein, Coronavirus / metabolism


  • Angiotensin-Converting Enzyme 2
  • Peptidyl-Dipeptidase A
  • Receptors, Transferrin
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • CD71 antigen