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Literature detail

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

Sarah Temmam1,2 Xavier Montagutelli3 Cécile Herate4 Flora Donati5,6 Béatrice Regnault1,2 Mikael Attia5 Eduard Baquero Salazar7 Delphine Chretien1,2 Laurine Conquet3 Grégory Jouvion8,9 Juliana Pipoli Da Fonseca10 Thomas Cokelaer10 Faustine Amara5 Francis Relouzat4 Thibaut Naninck4 Julien Lemaitre4 Nathalie Derreudre-Bosquet4 Quentin Pascal4 Massimiliano Bonomi11 Thomas Bigot1,12 Sandie Munier5 Felix A Rey7 Roger Le Grand4 Sylvie van der Werf5,6 Marc Eloit1,2,13
Affiliations 13 institutions
  1. Institut Pasteur, Université Paris Cité, Pathogen Discovery Laboratory, Paris, France.
  2. Institut Pasteur, Université Paris Cité, The OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Paris, France.
  3. Institut Pasteur, Université Paris Cité, Mouse Genetics Laboratory, Paris, France.
  4. Center for Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, Inserm, CEA, Fontenay-aux-Roses, France.
  5. Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Molecular Genetics of RNA Viruses Unit, Paris, France.
  6. Institut Pasteur, Université Paris Cité, National Reference Center for Respiratory Viruses, Paris, France.
  7. Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Structural Virology Unit, Paris, France.
  8. Ecole Nationale Vétérinaire d'Alfort, Unité d'Histologie et d'Anatomie Pathologique, Maisons-Alfort, France.
  9. Université Paris Est Créteil, EnvA, ANSES, Unité DYNAMYC, Créteil, France.
  10. Biomics Platform, C2RT, Institut Pasteur, Université Paris Cité, Paris, France.
  11. Institut Pasteur, Université Paris Cité, CNRS UMR 3528, Structural Bioinformatics Unit, Paris, France.
  12. Bioinformatic and Biostatistic Hub - Computational Biology Department, Institut Pasteur, Université Paris Cité, Paris, France.
  13. Ecole Nationale Vétérinaire d'Alfort, University of Paris-Est, Maisons-Alfort, France.
PMID 36876574 2023 EMBO Rep eng ppublish
PubMed DOI Browse context

Article

Publication summary

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.

adaptive mutations animal model bat coronavirus pathogenesis serology COVID-19 Animals Furin Humans Mice Mutation SARS-CoV-2 Spike Glycoprotein, Coronavirus spike protein, SARS-CoV-2

Structured evidence records

Evidence records

7 total
Host Range Experiment 5 records
Host Range Experiment Extraction confidence 0.95
Key finding

BANAL-236 infected human cells despite lacking the spike furin cleavage site.

Virus
SARSr-CoV
Location
Not specified
Supporting text

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.

Method
infection assay
Experimental system
in vitro cell culture
Host Range Experiment Extraction confidence 0.95
Key finding

BANAL-236 replicated efficiently with enteric tropism in humanized mice and macaques.

Virus
SARSr-CoV
Location
Not specified
Supporting text

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.

Method
experimental infection
Sample type
enteric tissues
Experimental system
in vivo animal experiment
Host Range Experiment Extraction confidence 0.95
Key finding

BANAL-236 replicated efficiently with enteric tropism in macaques.

Virus
SARSr-CoV
Location
Not specified
Supporting text

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.

Method
experimental infection
Sample type
enteric tissues
Experimental system
in vivo animal experiment
Host Range Experiment Extraction confidence 0.90
Key finding

Serial passage of BANAL-236 in humanized mice or human intestinal cells selected adaptive mutations but did not alter virulence.

Virus
SARSr-CoV
Location
Not specified
Supporting text

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.

Method
serial passage experiment
Sample type
intestinal cells
Experimental system
in vitro cell culture
Host Range Experiment Extraction confidence 0.90
Key finding

Serial passage of BANAL-236 in humanized mice selected adaptive mutations without changing virulence or producing a furin cleavage site.

Virus
SARSr-CoV
Location
Not specified
Supporting text

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.

Method
serial passage experiment
Experimental system
in vivo animal experiment
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.95
Key finding

Passaging of BANAL-236, a bat sarbecovirus highly related to SARS-CoV-2, in humanized mice or intestinal cells led to adaptive mutations in the spike protein without acquisition of a furin cleavage site or increased virulence.

Virus
SARSr-CoV
Host
Not specified
Location
Not specified
Supporting text

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.

Genes or proteins
spike
Mechanism types
replication_efficiency; pathogenicity; host_adaptation
Serological Evidence 1 records
Serological Evidence Extraction confidence 0.85
Key finding

No antibodies to bat sarbecoviruses were detected in human populations exposed to bats.

Virus
Sarbecovirus
Location
Not specified
Supporting text

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.

Method
serology
Sample type
serum