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Significance
SARS-CoV-2 has been detected in almost all organs of COVID-19 patients, although some of the organs express little or no ACE2. Single-cell sequencing indicates that SARS-CoV-2 is present in diverse immune cells, which do not express ACE2, suggesting the presence of other receptors/co-receptors mediating virus entry. Here, we identified human TfR, one of the most ubiquitously and highly expressed membrane components, as a receptor of SARS-CoV-2. TfR mediated SARS-CoV-2 infection by directly binding to the spike with high affinity and transporting the virus into the host cells. Interference with the TfR and SARS-CoV-2 interaction significantly inhibited viral infection. This study indicates that TfR is an alternative target for SARS-CoV-2 infection. The TfR trafficking pathway mediates SARS-CoV-2 entry and infectivity.
Abstract
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.
Published in PNAS (Feb. 26, 2024):
