Human Transferrin Receptor Can Mediate SARS-CoV-2 Infection

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2024 Feb 26

PMID 38408250

Authors

Zhiyi Liao

Chaoming Wang

Xiaopeng Tang

Mengli Yang

Zilei Duan

Lei Liu

Shuaiyao Lu

Lei Ma

Ruomei Cheng

Gan Wang

Hongqi Liu

Shuo Yang

Jingwen Xu

Dawit Adisu Tadese

James Mwangi

Peter Muiruri Kamau

Zhiye Zhang

Lian Yang

Guoyang Liao

Xudong Zhao

Xiaozhong Peng

Ren Lai

Affiliations

Soon will be listed here.

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 (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.

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