SARS‐CoV‐2‐related bat virus behavior in human‐relevant models sheds light on the origin of COVID‐19

Sarah Temmam (1, 2) , Xavier Montagutelli (3) , Cécile Herate (4) , Flora Donati (5, 6) , Béatrice Regnault (1, 2) , Mikael Attia (5) , Eduard Baquero Salazar (7) , Delphine Chretien (1, 2) , Laurine Conquet (3) , Grégory Jouvion (8, 9) , Juliana Pipoli da Fonseca (10) , Thomas Cokelaer (10) , Faustine Amara (5) , Francis Relouzat (4) , Thibaut Naninck (4) , Julien Lemaitre (4) , Nathalie Derreudre-Bosquet (4) , Quentin Pascal (4) , Massimiliano Bonomi (11) , Thomas Bigot (1, 12) , Sandie Munier (5) , Felix Rey (7) , Roger Le Grand (4) , Sylvie van der Werf (5, 6) , Marc Eloit (1, 2, 8)

1 Découverte de pathogènes – Pathogen discovery
2 CCOIE-OIECC - 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
3 Génétique de la souris - Mouse Genetics
4 IMVA-HB - Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes
5 GMV-ARN (UMR_3569 / U-Pasteur_2) - Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses
6 CNR - laboratoire coordonnateur - Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris]
7 Virologie Structurale - Structural Virology
8 ENVA - École nationale vétérinaire d'Alfort
9 DYNAMIC - Dynamic Microbiology - EA 7380
10 Biomics (plateforme technologique)
11 Bioinformatique structurale - Structural Bioinformatics
12 Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB

Bat sarbecovirus BANAL-236 is highly related to SARS-CoV-2 and infects human cells, albeit lacking the furin cleavage site in its spike protein. BANAL-236 replicates efficiently and pauci-symptomatically in humanized mice and in macaques, where its tropism is enteric, strongly differing from that of SARS-CoV-2. BANAL-236 infection leads to protection against superinfection by a virulent strain. We find no evidence of antibodies recognizing bat sarbecoviruses in populations in close contact with bats in which the virus was identified, indicating that such spillover infections, if they occur, are rare. Six passages in humanized mice or in human intestinal cells, mimicking putative early spillover events, select adaptive mutations without appearance of a furin cleavage site and no change in virulence. Therefore, acquisition of a furin site in the spike protein is likely a pre-spillover event that did not occur upon replication of a SARS-CoV-2-like bat virus in humans or other animals. Other hypotheses regarding the origin of the SARS-CoV-2 should therefore be evaluated, including the presence of sarbecoviruses carrying a spike with a furin cleavage site in bats.

Keywords: adaptive mutations; animal model; bat coronavirus; pathogenesis; serology

Domains: Environmental Sciences

Sarah Temmam, Xavier Montagutelli, Cécile Herate, Flora Donati, Béatrice Regnault, et al.. SARS‐CoV‐2‐related bat virus behavior in human‐relevant models sheds light on the origin of COVID‐19. EMBO Reports, 2023, 24 (4), pp.e56055. ⟨10.15252/embr.202256055⟩. ⟨pasteur-04072738⟩