TMPRSS2 is a functional receptor for human coronavirus HKU1

Nell Saunders, Ignacio Fernandez, Cyril Planchais, Vincent Michel, Maaran Michael Rajah, Eduard Baquero Salazar, Jeanne Postal, Francoise Porrot, Florence Guivel-Benhassine, Catherine Blanc, Gaëlle Chauveau-Le Friec, Augustin Martin, Ludivine Grzelak, Rischa Maya Oktavia, Annalisa Meola, Olivia Ahouzi, Hunter Hoover-Watson, Matthieu Prot, Deborah Delaune, Marion Cornelissen, Martin Deijs, Véronique Meriaux, Hugo Mouquet, Etienne Simon-Lorière, Lia Hoek, Pierre Lafaye, Felix Rey, Julian Buchrieser () and Olivier Schwartz ()
Additional contact information
Nell Saunders: Université de Paris Cité, CNRS UMR 3569
Ignacio Fernandez: Université de Paris Cité, CNRS UMR 3569
Cyril Planchais: Université de Paris Cité, INSERM U1222
Vincent Michel: Institut Pasteur, INSERM
Maaran Michael Rajah: Université de Paris Cité, CNRS UMR 3569
Eduard Baquero Salazar: Université de Paris Cité, INSERM U1222
Jeanne Postal: Université de Paris Cité, CNRS UMR 3569
Francoise Porrot: Université de Paris Cité, CNRS UMR 3569
Florence Guivel-Benhassine: Université de Paris Cité, CNRS UMR 3569
Catherine Blanc: Université de Paris Cité
Gaëlle Chauveau-Le Friec: Université de Paris Cité, CNRS UMR 3528
Augustin Martin: Université de Paris Cité, CNRS UMR 3569
Ludivine Grzelak: Université de Paris Cité, CNRS UMR 3569
Rischa Maya Oktavia: Université de Paris Cité, CNRS UMR 3569
Annalisa Meola: Université de Paris Cité, CNRS UMR 3569
Olivia Ahouzi: Université de Paris Cité, CNRS UMR 3569
Hunter Hoover-Watson: Université de Paris Cité, CNRS UMR 3569
Matthieu Prot: Institut Pasteur
Deborah Delaune: Institut Pasteur
Marion Cornelissen: University of Amsterdam
Martin Deijs: Amsterdam Institute for Infection and Immunity
Véronique Meriaux: Université de Paris Cité, CNRS UMR 3528
Hugo Mouquet: Université de Paris Cité, INSERM U1222
Etienne Simon-Lorière: Institut Pasteur
Lia Hoek: Amsterdam Institute for Infection and Immunity
Pierre Lafaye: Université de Paris Cité, CNRS UMR 3528
Felix Rey: Université de Paris Cité, CNRS UMR 3569
Julian Buchrieser: Université de Paris Cité, CNRS UMR 3569
Olivier Schwartz: Université de Paris Cité, CNRS UMR 3569

Nature, 2023, vol. 624, issue 7990, 207-214

Abstract: Abstract Four endemic seasonal human coronaviruses causing common colds circulate worldwide: HKU1, 229E, NL63 and OC43 (ref. 1). After binding to cellular receptors, coronavirus spike proteins are primed for fusion by transmembrane serine protease 2 (TMPRSS2) or endosomal cathepsins2–9. NL63 uses angiotensin-converting enzyme 2 as a receptor10, whereas 229E uses human aminopeptidase-N11. HKU1 and OC43 spikes bind cells through 9-O-acetylated sialic acid, but their protein receptors remain unknown12. Here we show that TMPRSS2 is a functional receptor for HKU1. TMPRSS2 triggers HKU1 spike-mediated cell–cell fusion and pseudovirus infection. Catalytically inactive TMPRSS2 mutants do not cleave HKU1 spike but allow pseudovirus infection. Furthermore, TMPRSS2 binds with high affinity to the HKU1 receptor binding domain (Kd 334 and 137 nM for HKU1A and HKU1B genotypes) but not to SARS-CoV-2. Conserved amino acids in the HKU1 receptor binding domain are essential for binding to TMPRSS2 and pseudovirus infection. Newly designed anti-TMPRSS2 nanobodies potently inhibit HKU1 spike attachment to TMPRSS2, fusion and pseudovirus infection. The nanobodies also reduce infection of primary human bronchial cells by an authentic HKU1 virus. Our findings illustrate the various evolution strategies of coronaviruses, which use TMPRSS2 to either directly bind to target cells or prime their spike for membrane fusion and entry.

Date: 2023
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DOI: 10.1038/s41586-023-06761-7

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