tetano
Editor, Senior Moderator
Nature
. 2023 Oct 25.
doi: 10.1038/s41586-023-06761-7. Online ahead of print. TMPRSS2 is a functional receptor for human coronavirus HKU1
Nell Saunders[SUP] 1 [/SUP], Ignacio Fernandez[SUP] 2 [/SUP], Cyril Planchais[SUP] 3 [/SUP], Vincent Michel[SUP] 4 [/SUP], Maaran Michael Rajah[SUP] 1 [/SUP], Eduard Baquero Salazar[SUP] 5 [/SUP], Jeanne Postal[SUP] 1 [/SUP], Francoise Porrot[SUP] 1 [/SUP], Florence Guivel-Benhassine[SUP] 1 [/SUP], Catherine Blanc[SUP] 6 [/SUP], Gaëlle Chauveau-Le Friec[SUP] 7 [/SUP], Augustin Martin[SUP] 1 [/SUP], Ludivine Grzelak[SUP] 1 [/SUP], Rischa Maya Oktavia[SUP] 2 [/SUP], Annalisa Meola[SUP] 2 [/SUP], Olivia Ahouzi[SUP] 2 [/SUP], Hunter Hoover-Watson[SUP] 1 [/SUP], Matthieu Prot[SUP] 8 [/SUP], Deborah Delaune[SUP] 8 9 [/SUP], Marion Cornelissen[SUP] 10 11 [/SUP], Martin Deijs[SUP] 11 12 [/SUP], Véronique Meriaux[SUP] 7 [/SUP], Hugo Mouquet[SUP] 3 [/SUP], Etienne Simon-Lorière[SUP] 8 13 [/SUP], Lia van der Hoek[SUP] 11 12 [/SUP], Pierre Lafaye[SUP] 7 [/SUP], Felix Rey[SUP] 2 [/SUP], Julian Buchrieser[SUP] #[/SUP][SUP] 14 [/SUP], Olivier Schwartz[SUP] #[/SUP][SUP] 15 16 [/SUP]
Affiliations
Four endemic seasonal human coronaviruses causing common colds, HKU1, 229E, NL63 and OC43 circulate worldwide[SUP]1[/SUP]. After binding to cellular receptors, coronavirus spike proteins are primed for fusion by transmembrane-serine protease 2 (TMPRSS2) or endosomal cathepsins[SUP]2-9[/SUP]. NL63 uses angiotensin-converting enzyme 2 (ACE2) as a receptor[SUP]10[/SUP], whereas 229E uses human aminopeptidase-N[SUP]11[/SUP]. HKU1 and OC43 spikes bind cells through 9-O40 acelytated sialic acid but their protein receptors remain unknown[SUP]12[/SUP]. Here, we show that TMPRSS2 is a functional receptor for HKU1. TMPRSS2 triggers HKU1 spike-mediated cell42 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 (RBD) (Kd 334 and 137 nM for HKU1A and HKU1B genotypes) but not to SARS-CoV-2. Conserved amino acids within HKU1 RBD 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 HKU-1 virus. Our findings illustrate the various evolution strategies of coronaviruses, which use TMPRSS2 to either directly bind to target cells or to prime their spike for membrane fusion and entry.
. 2023 Oct 25.
doi: 10.1038/s41586-023-06761-7. Online ahead of print. TMPRSS2 is a functional receptor for human coronavirus HKU1
Nell Saunders[SUP] 1 [/SUP], Ignacio Fernandez[SUP] 2 [/SUP], Cyril Planchais[SUP] 3 [/SUP], Vincent Michel[SUP] 4 [/SUP], Maaran Michael Rajah[SUP] 1 [/SUP], Eduard Baquero Salazar[SUP] 5 [/SUP], Jeanne Postal[SUP] 1 [/SUP], Francoise Porrot[SUP] 1 [/SUP], Florence Guivel-Benhassine[SUP] 1 [/SUP], Catherine Blanc[SUP] 6 [/SUP], Gaëlle Chauveau-Le Friec[SUP] 7 [/SUP], Augustin Martin[SUP] 1 [/SUP], Ludivine Grzelak[SUP] 1 [/SUP], Rischa Maya Oktavia[SUP] 2 [/SUP], Annalisa Meola[SUP] 2 [/SUP], Olivia Ahouzi[SUP] 2 [/SUP], Hunter Hoover-Watson[SUP] 1 [/SUP], Matthieu Prot[SUP] 8 [/SUP], Deborah Delaune[SUP] 8 9 [/SUP], Marion Cornelissen[SUP] 10 11 [/SUP], Martin Deijs[SUP] 11 12 [/SUP], Véronique Meriaux[SUP] 7 [/SUP], Hugo Mouquet[SUP] 3 [/SUP], Etienne Simon-Lorière[SUP] 8 13 [/SUP], Lia van der Hoek[SUP] 11 12 [/SUP], Pierre Lafaye[SUP] 7 [/SUP], Felix Rey[SUP] 2 [/SUP], Julian Buchrieser[SUP] #[/SUP][SUP] 14 [/SUP], Olivier Schwartz[SUP] #[/SUP][SUP] 15 16 [/SUP]
Affiliations
- PMID: 37879362
- DOI: 10.1038/s41586-023-06761-7
Four endemic seasonal human coronaviruses causing common colds, HKU1, 229E, NL63 and OC43 circulate worldwide[SUP]1[/SUP]. After binding to cellular receptors, coronavirus spike proteins are primed for fusion by transmembrane-serine protease 2 (TMPRSS2) or endosomal cathepsins[SUP]2-9[/SUP]. NL63 uses angiotensin-converting enzyme 2 (ACE2) as a receptor[SUP]10[/SUP], whereas 229E uses human aminopeptidase-N[SUP]11[/SUP]. HKU1 and OC43 spikes bind cells through 9-O40 acelytated sialic acid but their protein receptors remain unknown[SUP]12[/SUP]. Here, we show that TMPRSS2 is a functional receptor for HKU1. TMPRSS2 triggers HKU1 spike-mediated cell42 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 (RBD) (Kd 334 and 137 nM for HKU1A and HKU1B genotypes) but not to SARS-CoV-2. Conserved amino acids within HKU1 RBD 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 HKU-1 virus. Our findings illustrate the various evolution strategies of coronaviruses, which use TMPRSS2 to either directly bind to target cells or to prime their spike for membrane fusion and entry.