Early innate immune response and evolution of a SARS-CoV-2 furin cleavage site inactive variant in bat cells

doi:10.1016/j.celrep.2025.115929

. 2025 Jul 22;44(7):115929.

doi: 10.1016/j.celrep.2025.115929. Epub 2025 Jul 1.

Early innate immune response and evolution of a SARS-CoV-2 furin cleavage site inactive variant in bat cells

Kaushal Baid¹, Sauhard Shrivastava², Jessica Luc³, Daniel Richard⁴, Jennifer A Aguiar³, Yoan Machado⁵, Sophie-Marie Aicher⁶, Kimberley C Siwak⁷, Emmanuelle V LeBlanc⁷, Zahed Khatooni¹, Kumari G Lokugamage⁸, Michelle N Vu⁸, Angelica Morgan⁸, Arkadeb Bhuinya², Kim R Chiok¹, Hai T Nguyen¹, Hannah D Stacey⁹, Erin Scruten¹, Tracy Prysliak¹, Winfield Yim¹⁰, Andrew G McArthur¹¹, Matthew S Miller⁹, Heather L Wilson², Terence Capellini⁴, Paul A Faure¹², Qiang Liu², Samira Mubareka¹⁰, Vineet D Menachery⁸, Karen Mossman¹³, Marcel A Müller¹⁴, Christian Drosten¹⁴, Che C Colpitts⁷, Nolwenn Jouvenet⁶, Christopher M Overall⁵, Andrew C Doxey¹⁵, Arinjay Banerjee¹⁶

Affiliations

¹ Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, SK, Canada.
² Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, SK, Canada; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
³ Department of Biology, University of Waterloo, Waterloo, ON, Canada.
⁴ Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.
⁵ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; Centre for Blood Research, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada; Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada.
⁶ Institut Pasteur, Université de Paris, CNRS UMR3569, Virus Sensing and Signaling Unit, Paris, France.
⁷ Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
⁸ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, USA; Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, USA.
⁹ Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
¹⁰ Sunnybrook Research Institute, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹¹ Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
¹² Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, ON, Canada.
¹³ Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada.
¹⁴ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, Berlin, Germany; German Center for Infection Research (DZIF), Partner Site Charité, Berlin, Germany.
¹⁵ Department of Biology, University of Waterloo, Waterloo, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada. Electronic address: acdoxey@uwaterloo.ca.
¹⁶ Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, SK, Canada; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada; Department of Biology, University of Waterloo, Waterloo, ON, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address: arinjay.banerjee@usask.ca.

PMID: 40608518
DOI: 10.1016/j.celrep.2025.115929

Free article

Early innate immune response and evolution of a SARS-CoV-2 furin cleavage site inactive variant in bat cells

Kaushal Baid et al. Cell Rep. 2025.

Free article

. 2025 Jul 22;44(7):115929.

doi: 10.1016/j.celrep.2025.115929. Epub 2025 Jul 1.

Authors

Affiliations

¹ Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, SK, Canada.
² Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, SK, Canada; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
³ Department of Biology, University of Waterloo, Waterloo, ON, Canada.
⁴ Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.
⁵ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; Centre for Blood Research, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada; Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada.
⁶ Institut Pasteur, Université de Paris, CNRS UMR3569, Virus Sensing and Signaling Unit, Paris, France.
⁷ Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
⁸ Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, USA; Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX, USA.
⁹ Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
¹⁰ Sunnybrook Research Institute, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹¹ Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
¹² Department of Psychology, Neuroscience & Behaviour, McMaster University, Hamilton, ON, Canada.
¹³ Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada.
¹⁴ Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, Berlin, Germany; German Center for Infection Research (DZIF), Partner Site Charité, Berlin, Germany.
¹⁵ Department of Biology, University of Waterloo, Waterloo, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada. Electronic address: acdoxey@uwaterloo.ca.
¹⁶ Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, SK, Canada; Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada; Department of Biology, University of Waterloo, Waterloo, ON, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address: arinjay.banerjee@usask.ca.

PMID: 40608518
DOI: 10.1016/j.celrep.2025.115929

Abstract

SARS-CoV-2 has caused the largest known coronavirus pandemic and is believed to have emerged from insectivorous bats. Little is known about the evolution of these viruses in their reservoir bat species. In this study, we investigate the SARS-CoV-2-host interaction using human and bat cells. Bat cells mount a robust and early antiviral response but elicit a dampened proinflammatory response upon SARS-CoV-2 infection compared to human cells. Furthermore, an inactivating R685P mutation within the furin cleavage site (FCS) of the SARS-CoV-2 spike protein is naturally selected for in infected bat cells. Taken together, our data demonstrate that insectivorous Eptesicus fuscus bat cells have evolved a differential antiviral immune response against SARS-CoV-2 infection, likely contributing to their disease tolerance ability. Our study sheds light on the evolution of sarbecoviruses in bats and extends molecular evidence to data from field studies that have demonstrated that SARS-CoV-2-related viruses in wild-caught bats lack an intact FCS.

Keywords: CP: Immunology; CP: Microbiology; SARS-CoV-2; antiviral response; bats; coronavirus; furin cleavage site; proteomics; reservoir host; transcriptomics; zoonosis.

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Conflict of interest statement

Declaration of interests A. Banerjee is a co-inventor of the Efk3B cell line, which is sold through Kerafast, USA.

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Early innate immune response and evolution of a SARS-CoV-2 furin cleavage site inactive variant in bat cells

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Early innate immune response and evolution of a SARS-CoV-2 furin cleavage site inactive variant in bat cells

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