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SARS-CoV-2 infection, neuropathogenesis and transmission among deer mice: Implications for reverse zoonosis to New World rodents

Anna Fagre, Juliette Lewis, Miles Eckley, Shijun Zhan, Savannah M Rocha, Nicole R Sexton, Bradly Burke, Brian Geiss, Olve Peersen, Rebekah Kading, Joel Rovnak, Gregory D Ebel, Ronald B Tjalkens, Tawfik Aboellail, View ORCID ProfileTony Schountz
doi: https://doi.org/10.1101/2020.08.07.241810
Anna Fagre
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Juliette Lewis
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Miles Eckley
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Shijun Zhan
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Savannah M Rocha
2Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Nicole R Sexton
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Bradly Burke
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Brian Geiss
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Olve Peersen
3Department of Biochemistry and Molecular Biology, College of Natural Sciences, Colorado State University, Fort Collins, CO 80523
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Rebekah Kading
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Joel Rovnak
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Gregory D Ebel
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Ronald B Tjalkens
2Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Tawfik Aboellail
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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Tony Schountz
1Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523
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  • ORCID record for Tony Schountz
  • For correspondence: tony.schountz@colostate.edu
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Abstract

Coronavirus disease-19 (COVID-19) emerged in November, 2019 in China and rapidly became pandemic. As with other coronaviruses, a preponderance of evidence suggests the virus originated in horseshoe bats (Rhinolophus spp.) and likely underwent a recombination event in an intermediate host prior to entry into human populations. A significant concern is that SARS-CoV-2 could become established in secondary reservoir hosts outside of Asia. To assess this potential, we challenged deer mice (Peromyscus maniculatus) with SARS-CoV-2 and found robust virus replication in the upper respiratory tract, lungs and intestines, with detectable viral RNA for up to 21 days in oral swabs and 14 days in lungs. Virus entry into the brain also occurred, likely via gustatory-olfactory-trigeminal pathway with eventual compromise to the blood brain barrier. Despite this, no conspicuous signs of disease were observed and no deer mice succumbed to infection. Expression of several innate immune response genes were elevated in the lungs, notably IFNα, Cxcl10, Oas2, Tbk1 and Pycard. Elevated CD4 and CD8β expression in the lungs was concomitant with Tbx21, IFNγ and IL-21 expression, suggesting a type I inflammatory immune response. Contact transmission occurred from infected to naive deer mice through two passages, showing sustained natural transmission. In the second deer mouse passage, an insertion of 4 amino acids occurred to fixation in the N-terminal domain of the spike protein that is predicted to form a solvent-accessible loop. Subsequent examination of the source virus from BEI Resources indicated the mutation was present at very low levels, demonstrating potent purifying selection for the insert during in vivo passage. Collectively, this work has determined that deer mice are a suitable animal model for the study of SARS-CoV-2 pathogenesis, and that they have the potential to serve as secondary reservoir hosts that could lead to periodic outbreaks of COVID-19 in North America.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 07, 2020.
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SARS-CoV-2 infection, neuropathogenesis and transmission among deer mice: Implications for reverse zoonosis to New World rodents
Anna Fagre, Juliette Lewis, Miles Eckley, Shijun Zhan, Savannah M Rocha, Nicole R Sexton, Bradly Burke, Brian Geiss, Olve Peersen, Rebekah Kading, Joel Rovnak, Gregory D Ebel, Ronald B Tjalkens, Tawfik Aboellail, Tony Schountz
bioRxiv 2020.08.07.241810; doi: https://doi.org/10.1101/2020.08.07.241810
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SARS-CoV-2 infection, neuropathogenesis and transmission among deer mice: Implications for reverse zoonosis to New World rodents
Anna Fagre, Juliette Lewis, Miles Eckley, Shijun Zhan, Savannah M Rocha, Nicole R Sexton, Bradly Burke, Brian Geiss, Olve Peersen, Rebekah Kading, Joel Rovnak, Gregory D Ebel, Ronald B Tjalkens, Tawfik Aboellail, Tony Schountz
bioRxiv 2020.08.07.241810; doi: https://doi.org/10.1101/2020.08.07.241810

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