OmniVira

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.
PMID36876574 DOI10.15252/embr.202256055 Year2023 Journal EMBO reports EMBO Rep Languageeng Statusppublish

Abstract

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.

Supporting text Virus Host Location
adaptive mutations 3 animal model 5 bat coronavirus 8 pathogenesis 12 serology 50 COVID-19 425 Animals 1948 Furin 14 Humans 1440 Mice 253 Mutation 209 SARS-CoV-2 453 Spike Glycoprotein, Coronavirus 274 spike protein, SARS-CoV-2 157

Evidence records

4 total
Zoonotic Surveillance
1 records · 1 evidence types
Evidence type Serological Evidence
1 records
OVE6813 Serological Evidence
Key finding

No antibodies recognizing bat sarbecoviruses were detected in human populations that are in close contact with bats where the virus was identified.

Virus
Sarbecovirus
Host
human Homo sapiens Natural host
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
antibody detection | serological screening
Sample type
serum
Experimental Infection
3 records · 2 evidence types
Evidence type Pathogenicity Experiment
1 records
OVE6812 Pathogenicity Experiment
Key finding

BANAL-236 caused mild disease and showed enteric tropism in experimentally infected humanized mice and macaques.

Virus
SARS-related coronavirus
Host
house mouse Mus musculus Experimental system macaques Macaca Experimental system
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 | monitoring of clinical signs | tissue tropism analysis
Experimental system
animal infection models (humanized mice and macaques)
Evidence type Host Range Experiment
2 records
OVE6809 Host Range Experiment
Key finding

Bat sarbecovirus BANAL-236 was experimentally shown to infect human cells despite lacking the spike furin cleavage site.

Virus
SARS-related coronavirus
Host
human cells Homo sapiens Experimental system bats Chiroptera Natural host
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
experimental infection | cell culture assay | virus entry and replication analysis
Experimental system
cell-culture infection model
OVE6810 Host Range Experiment
Key finding

BANAL-236 replicated efficiently and with limited symptoms in humanized mice and macaques, exhibiting enteric tropism distinct from SARS-CoV-2.

Virus
SARS-related coronavirus
Host
house mouse Mus musculus Experimental system macaques Macaca Experimental system bats Chiroptera Natural host
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
in vivo infection | viral replication assay | pathology observation
Sample type
intestinal tissues
Experimental system
animal challenge models