TMPRSS2 is a functional receptor for human coronavirus HKU1

Nell Saunders (1) , Ignacio Fernandez (2) , Cyril Planchais (3) , Vincent Michel (4) , Maaran Michael Rajah (1) , Eduard Baquero Salazar (5) , Jeanne Postal (1) , Francoise Porrot (1) , Florence Guivel-Benhassine (1) , Catherine Blanc (6) , Gaëlle Chauveau-Le Friec (7) , Augustin Martin (1) , Ludivine Grzelak (1) , Rischa Maya Oktavia (2) , Annalisa Meola (2) , Olivia Ahouzi (2) , Hunter Hoover-Watson (1) , Matthieu Prot (8) , Deborah Delaune (8, 9) , Marion Cornelissen (10, 11) , Martin Deijs (11) , Véronique Meriaux (7) , Hugo Mouquet (3) , Etienne Simon-Lorière (8, 12) , Lia van der Hoek (11) , Pierre Lafaye (7) , Felix Rey (2) , Julian Buchrieser (1) , Olivier Schwartz (13)

1 CNRS-UMR3569 - Virus et Immunité - Virus and immunity
2 Virologie Structurale - Structural Virology
3 Immunologie humorale - Humoral Immunology
4 Pathogénèse des Infections vasculaires / Pathogenesis of Vascular Infections
5 Plateforme technologique Nanoimagerie / Nanoimaging Technological Platform
6 Laboratoire commun Pasteur-TheraVectys
7 Ingénierie des Anticorps (plate-forme) - Antibody Engineering (Platform)
8 Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses
9 IRBA - Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge]
10 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
11 Amsterdam UMC - Amsterdam University Medical Center
12 CNR - laboratoire coordonnateur - Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris]
13 VRI - Vaccine Research Institute [Créteil, France]

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 cathepsins2,3,4,5,6,7,8,9. 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.

Domaines: Virologie; Maladies émergentes; Maladies infectieuses

Nell Saunders, Ignacio Fernandez, Cyril Planchais, Vincent Michel, Maaran Michael Rajah, et al.. TMPRSS2 is a functional receptor for human coronavirus HKU1. Nature, 2023, 624 (7990), pp.207-214. ⟨10.1038/s41586-023-06761-7⟩. ⟨hal-04372694⟩