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TMPRSS2 is a functional receptor for human coronavirus HKU1
Nell Saunders1, Ignacio Fernandez2, Cyril Planchais3
1Virus & Immunity Unit, Institut Pasteur, Université de Paris Cité, CNRS UMR 3569, Paris, France.
Nature
|October 25, 2023
Summary
Transmembrane serine protease 2 (TMPRSS2) acts as a direct receptor for the HKU1 coronavirus, facilitating cell entry and infection. This discovery reveals a novel viral binding strategy and potential therapeutic target for common cold coronaviruses.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Four endemic human coronaviruses (HKU1, 229E, NL63, OC43) cause common colds globally.
- Coronavirus entry relies on spike protein priming by cellular proteases like TMPRSS2 or cathepsins.
- Receptors for HKU1 and OC43 spikes remain unidentified, unlike NL63 (ACE2) and 229E (hAPN).
Purpose of the Study:
- To identify the cellular receptor for the HKU1 coronavirus.
- To elucidate the mechanism of HKU1 entry and potential therapeutic interventions.
Main Methods:
- Investigated TMPRSS2 as a functional receptor for HKU1.
- Assessed HKU1 spike-mediated cell-cell fusion and pseudovirus infection.
- Utilized catalytically inactive TMPRSS2 mutants and anti-TMPRSS2 nanobodies.
- Performed binding affinity studies and tested inhibition of authentic HKU1 virus infection.
Main Results:
- TMPRSS2 directly binds to the HKU1 spike protein, acting as a functional receptor.
- TMPRSS2 triggers HKU1 spike-mediated cell-cell fusion and pseudovirus infection.
- Anti-TMPRSS2 nanobodies effectively inhibit HKU1 attachment, fusion, and infection in cell cultures and primary bronchial cells.
Conclusions:
- TMPRSS2 serves as a direct receptor for HKU1, distinct from its role in priming other coronaviruses.
- This finding highlights diverse coronavirus evolutionary strategies for cell binding and entry.
- Targeting TMPRSS2 with nanobodies presents a promising therapeutic strategy against HKU1 infections.
