Human transferrin receptor can mediate SARS-CoV-2 infection

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 (K_D ~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.