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SARS-CoV-2 infection of olfactory epithelial cells and neurons drives acute lung injury and lethal COVID-19 in mice

Alan T. Tang, David W. Buchholz, Katherine M. Szigety, Brian Imbhiaka, Siqi Gao, Maxwell Frankfurter, Min Wang, Jisheng Yang, Peter Hewins, Patricia Mericko-Ishizuka, N Adrian Leu, Stephanie Sterling, Isaac A. Monreal, Julie Sahler, Avery August, Xuming Zhu, Kellie A. Jurado, Mingang Xu, Edward E. Morrisey, View ORCID ProfileSarah E. Millar, Hector C. Aguilar, View ORCID ProfileMark L. Kahn
doi: https://doi.org/10.1101/2021.12.04.471245
Alan T. Tang
1Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania, USA
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David W. Buchholz
2Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
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Katherine M. Szigety
1Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania, USA
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Brian Imbhiaka
2Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
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Siqi Gao
1Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania, USA
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Maxwell Frankfurter
1Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania, USA
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Min Wang
1Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania, USA
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Jisheng Yang
1Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania, USA
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Peter Hewins
3Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
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Patricia Mericko-Ishizuka
1Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania, USA
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N Adrian Leu
4Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Stephanie Sterling
4Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Isaac A. Monreal
2Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
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Julie Sahler
2Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
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Avery August
2Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
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Xuming Zhu
5Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Kellie A. Jurado
3Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
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Mingang Xu
5Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Edward E. Morrisey
1Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania, USA
6Penn-CHOP Lung Biology Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Sarah E. Millar
5Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
7Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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  • ORCID record for Sarah E. Millar
Hector C. Aguilar
1Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania, USA
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  • For correspondence: ha363@cornell.edu markkahn@pennmedicine.upenn.edu
Mark L. Kahn
1Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania, USA
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  • ORCID record for Mark L. Kahn
  • For correspondence: ha363@cornell.edu markkahn@pennmedicine.upenn.edu
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Abstract

Lethal COVID-19 is associated with respiratory failure that is thought to be caused by acute respiratory distress syndrome (ARDS) secondary to pulmonary infection. To date, the cellular pathogenesis has been inferred from studies describing the expression of ACE2, a transmembrane protein required for SARS-CoV-2 infection, and detection of viral RNA or protein in infected humans, model animals, and cultured cells. To functionally test the cellular mechanisms of COVID-19, we generated hACE2fl animals in which human ACE2 (hACE2) is expressed from the mouse Ace2 locus in a manner that permits cell-specific, Cre-mediated loss of function. hACE2fl animals developed lethal weight loss and hypoxemia within 7 days of exposure to SARS-CoV-2 that was associated with pulmonary infiltrates, intravascular thrombosis and patchy viral infection of lung epithelial cells. Deletion of hACE2 in lung epithelial cells prevented viral infection of the lung, but not weight loss, hypoxemia or death. Inhalation of SARS-CoV-2 by hACE2fl animals resulted in early infection of sustentacular cells with subsequent infection of neurons in the neighboring olfactory bulb and cerebral cortex— events that did not require lung epithelial cell infection. Pharmacologic ablation of the olfactory epithelium or Foxg1Cre mediated deletion of hACE2 in olfactory epithelial cells and neurons prevented lethality and neuronal infection following SARS-CoV-2 infection. Conversely, transgenic expression of hACE2 specifically in olfactory epithelial cells and neurons in Foxg1Cre; LSL-hACE2 mice was sufficient to confer neuronal infection associated with respiratory failure and death. These studies establish mouse loss and gain of function genetic models with which to genetically dissect viral-host interactions and demonstrate that lethal disease due to respiratory failure may arise from extrapulmonary infection of the olfactory epithelium and brain. Future therapeutic efforts focused on preventing olfactory epithelial infection may be an effective means of protecting against severe COVID-19.

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. All rights reserved. No reuse allowed without permission.
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Posted December 07, 2021.
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SARS-CoV-2 infection of olfactory epithelial cells and neurons drives acute lung injury and lethal COVID-19 in mice
Alan T. Tang, David W. Buchholz, Katherine M. Szigety, Brian Imbhiaka, Siqi Gao, Maxwell Frankfurter, Min Wang, Jisheng Yang, Peter Hewins, Patricia Mericko-Ishizuka, N Adrian Leu, Stephanie Sterling, Isaac A. Monreal, Julie Sahler, Avery August, Xuming Zhu, Kellie A. Jurado, Mingang Xu, Edward E. Morrisey, Sarah E. Millar, Hector C. Aguilar, Mark L. Kahn
bioRxiv 2021.12.04.471245; doi: https://doi.org/10.1101/2021.12.04.471245
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SARS-CoV-2 infection of olfactory epithelial cells and neurons drives acute lung injury and lethal COVID-19 in mice
Alan T. Tang, David W. Buchholz, Katherine M. Szigety, Brian Imbhiaka, Siqi Gao, Maxwell Frankfurter, Min Wang, Jisheng Yang, Peter Hewins, Patricia Mericko-Ishizuka, N Adrian Leu, Stephanie Sterling, Isaac A. Monreal, Julie Sahler, Avery August, Xuming Zhu, Kellie A. Jurado, Mingang Xu, Edward E. Morrisey, Sarah E. Millar, Hector C. Aguilar, Mark L. Kahn
bioRxiv 2021.12.04.471245; doi: https://doi.org/10.1101/2021.12.04.471245

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