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Human transferrin receptor can mediate SARS-CoV-2 infection
Zhiyi Liao1,2, Chaoming Wang1,2, Xiaopeng Tang1,3
1Engineering 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.
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.
Insights
The human transferrin receptor (TfR) acts as an alternative entry point for SARS-CoV-2, independent of ACE2. Targeting TfR shows promise for developing new COVID-19 therapies.
Area of Science:
- Virology
- Cell Biology
- Immunology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects various organs, yet the absence of angiotensin-converting enzyme-2 (ACE2) in some suggests alternative viral entry mechanisms.
- The ubiquitously expressed human transferrin receptor (TfR) is crucial for iron uptake via endocytosis.
Purpose of the Study:
- To investigate the role of human transferrin receptor (TfR) as an alternative receptor for SARS-CoV-2 entry.
- To explore TfR-targeted strategies for inhibiting SARS-CoV-2 infection.
Main Methods:
- Assessed SARS-CoV-2 interaction with human TfR using binding assays and measured viral infectivity in cells with varying TfR expression levels.
- Utilized TfR knockdown and overexpression models, along with humanized TfR expression in resistant cell lines and animal models.
- Evaluated the efficacy of soluble TfR, Tf-derived peptides, and anti-TfR antibodies against SARS-CoV-2 in vitro and in vivo.
Main Results:
- Human TfR binds SARS-CoV-2 Spike protein with high affinity (KD ~2.95 nM), mediating ACE2-independent viral endocytosis.
- TfR expression levels directly correlate with SARS-CoV-2 infectivity; TfR knockdown inhibits, while overexpression enhances infection.
- Humanized TfR expression confers SARS-CoV-2 susceptibility to resistant cells and animal models (baby hamster kidney cells, C57 mice).
- Therapeutic interventions targeting the TfR-Spike interaction (soluble TfR, peptides, antibodies) demonstrated significant anti-COVID-19 effects in cell and primate models.
Conclusions:
- Human transferrin receptor (TfR) serves as a critical ACE2-independent receptor or co-receptor for SARS-CoV-2 entry.
- TfR facilitates viral infection by likely utilizing the TfR-mediated endocytosis and trafficking pathway.
- Targeting TfR presents a viable therapeutic strategy against SARS-CoV-2 and potentially other viral infections.
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