TY - JOUR
T1 - TMPRSS2 is a functional receptor for human coronavirus HKU1
AU - Saunders, Nell
AU - Fernandez, Ignacio
AU - Planchais, Cyril
AU - Michel, Vincent
AU - Rajah, Maaran Michael
AU - Baquero Salazar, Eduard
AU - Postal, Jeanne
AU - Porrot, Francoise
AU - Guivel-Benhassine, Florence
AU - Blanc, Catherine
AU - Chauveau-Le Friec, Gaëlle
AU - Martin, Augustin
AU - Grzelak, Ludivine
AU - Oktavia, Rischa Maya
AU - Meola, Annalisa
AU - Ahouzi, Olivia
AU - Hoover-Watson, Hunter
AU - Prot, Matthieu
AU - Delaune, Deborah
AU - Cornelissen, Marion
AU - Deijs, Martin
AU - Meriaux, Véronique
AU - Mouquet, Hugo
AU - Simon-Lorière, Etienne
AU - van der Hoek, Lia
AU - Lafaye, Pierre
AU - Rey, Felix
AU - Buchrieser, Julian
AU - Schwartz, Olivier
N1 - Funding Information: We thank A. Amara, T. Bruel and N. Casartelli for critical reading of the manuscript, members of the Virus and Immunity Unit for discussions and help, N. Aulner, N. Mahtal and the UtechS Photonic BioImaging core facility (Institut Pasteur), P. Charneau for help in lentiviral pseudotype preparation and S. Pöhlmann for the kind gift of plasmids. N.S. is funded by the Ministère de l’Enseignement supérieur et de la Recherche. O.S.’s laboratory is funded by Institut Pasteur, Fondation pour la Recherche Médicale, the National Agency for AIDS Research–Emerging Infectious Diseases, the Vaccine Research Institute (ANR-10-LABX-77), Humanities in the European Research Area programme (DURABLE consortium), Labex Integrative Biology of Emerging Infectious Diseases (IBEID) (ANR-10-LABX-62-IBEID), Agence Nationale de la Recherche (ANR)/Fondation pour la Recherche Médicale Flash Covid PROTEO-SARS-CoV-2 and IDISCOVR. E.S.-L.’s lab is funded by the INCEPTION programme (Investissements d’Avenir grant no. ANR-16-CONV-0005), the National Institutes of Health Pasteur International Center for Research on Emerging Infectious Diseases programme (award no. U01AI151758), the Health Emergency Preparedness and Response European programme DURABLE (101102733) and the Labex IBEID (ANR-10-LABX-62-IBEID). H.M.’s laboratory is funded by the Institut Pasteur, the Milieu Intérieur Programme (ANR-10-LABX-69-01) and L'Institut national de la santé et de la recherche médicale, REACTing and European Union (Rapid European COVID-19 Emergency Response (RECOVER)) grants. M.M.R. was supported by the Pasteur-Paris University International Doctoral Programme and the Institut Pasteur Department of Virology ‘Bourse de Soudure’ fellowship. F.R.’s laboratory is funded by ANR grant nos. ANR-13-ISV8-0002-01 and ANR-10-LABX-62-10 IBEID, Wellcome Trust collaborative grant no. UNS22082 and the Institut Pasteur and the Centre national de la recherche scientifique. Work with UtechS Photonic BioImaging is funded by grant no. ANR-10-INSB-04-01 and Région Ile-de-France programme DIM1-Health. The funders of this study had no role in study design, data collection, analysis and interpretation or writing of this Article. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/12/7
Y1 - 2023/12/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85177734894&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41586-023-06761-7
DO - https://doi.org/10.1038/s41586-023-06761-7
M3 - Article
C2 - 37879362
SN - 0028-0836
VL - 624
SP - 207
EP - 214
JO - NATURE
JF - NATURE
IS - 7990
ER -