Contributors: Découverte de pathogènes – Pathogen discovery; Institut Pasteur Paris (IP)-Université Paris Cité (UPCité); Centre Collaborateur de l'OIE de Détection et identification chez l’homme des pathogènes animaux émergents et développement d’outils pour leur diagnostic / Collaborating Center for the Detection and identification in humans of emerging animal pathogens and development of tools for their diagnoses (CCOIE-OIECC); Institut Pasteur Paris (IP)-Organisation Mondiale de la Santé Animale / World Organisation Animal Health Paris (OIE)-Université Paris Cité (UPCité); Institut Pasteur du Laos; Pasteur Network (Réseau International des Instituts Pasteur); Virologie Structurale - Structural Virology; Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité); Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)); Bioinformatique structurale - Structural Bioinformatics; National University of Laos; Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae Paris (CNR - laboratoire coordonnateur); Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB; École nationale vétérinaire d'Alfort (ENVA); NGS was performed with the help of the Biomics Platform, Center for Technological Resources and Research, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09), Inclusive Blockchain Insurance using Space Assets and the Illumina COVID-19 Projects’ offer. The work was granted access to the High Performance Computing resources of the Institute for Development and Resources in Intensive Scientific Computing under the allocation 2020-101592 made by Grand Équipement National de Calcul Intensif. We thank the Ministry of Health and the Ministry of Natural Resources and Environments, Lao People’s Democratic Republic, for their authorization of the field work and the Faculty of Environmental Science for its authorization of the field research collaboration. The work was supported by an Institut Pasteur 'Covid Taskforce' and in part by the H2020 project 101003589 (RECOVER) and Labex IBEID (ANR-10-LABX62-IBEID) grants. Field and laboratory work at IPL was also supported by a UK embassy grant (grant no. INT 2021/LOV C19 02) and a Luxembourg Development special grant (grant no. LAO/030·202324).; We thank S. Mohamed Ali, N. Da Rocha, A. Brisebarre, T. Xaybounsou and S. Chonephetsarath for their help at the bench; A. Haouz and the staff of the protein crystallogenesis facility at Institut Pasteur for help with crystallization trials; P. England from the Molecular Biophysics facility at Institut Pasteur for his support and access to the BLI equipment; P. Legrand from the PX1 beamline at Synchrotron SOLEIL for data collection support; and P. Guardado-Calvo for discussion and support with BLI experiments.; ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010); ANR-10-INBS-0009,France Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010); European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020)
نبذة مختصرة : International audience ; The animal reservoir of SARS-CoV-2 is unknown despite reports of SARS-CoV-2-related viruses in Asian Rhinolophus bats1-4, including the closest virus from R. affinis, RaTG13 (refs. 5,6), and pangolins7-9. SARS-CoV-2 has a mosaic genome, to which different progenitors contribute. The spike sequence determines the binding affinity and accessibility of its receptor-binding domain to the cellular angiotensin-converting enzyme 2 (ACE2) receptor and is responsible for host range10-12. SARS-CoV-2 progenitor bat viruses genetically close to SARS-CoV-2 and able to enter human cells through a human ACE2 (hACE2) pathway have not yet been identified, although they would be key in understanding the origin of the epidemic. Here we show that such viruses circulate in cave bats living in the limestone karstic terrain in northern Laos, in the Indochinese peninsula. We found that the receptor-binding domains of these viruses differ from that of SARS-CoV-2 by only one or two residues at the interface with ACE2, bind more efficiently to the hACE2 protein than that of the SARS-CoV-2 strain isolated in Wuhan from early human cases, and mediate hACE2-dependent entry and replication in human cells, which is inhibited by antibodies that neutralize SARS-CoV-2. None of these bat viruses contains a furin cleavage site in the spike protein. Our findings therefore indicate that bat-borne SARS-CoV-2-like viruses that are potentially infectious for humans circulate in Rhinolophus spp. in the Indochinese peninsula.
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