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Lethality of SARS-CoV-2 infection in K18 human angiotensin converting enzyme 2 transgenic mice

Fatai S. Oladunni, Jun-Gyu Park, Paula Pino Tamayo, Olga Gonzalez, Anwari Akhter, Anna Allué-Guardia, Angélica Olmo-Fontánez, Shalini Gautam, Andreu Garcia-Vilanova, Chengjin Ye, Kevin Chiem, Colwyn Headley, Varun Dwivedi, Laura M. Parodi, Kendra J. Alfson, Hilary M. Staples, Alyssa Schami, Juan I. Garcia, Alison Whigham, Roy Neal Platt II, Michal Gazi, Jesse Martinez, Colin Chuba, Stephanie Earley, Oscar H Rodriguez, Stephanie Davis Mdaki, Katrina N Kavelish, Renee Escalona, Cory R. A. Hallam, Corbett Christie, Jean L. Patterson, View ORCID ProfileTim J. C. Anderson, Ricardo Carrion Jr, Edward J. Dick Jr, Shannan Hall-Ursone, Larry S. Schlesinger, Deepak Kaushal, Luis D. Giavedoni, Xavier Alvarez, Joanne Turner, Luis Martinez-Sobrido, Jordi B. Torrelles
doi: https://doi.org/10.1101/2020.07.18.210179
Fatai S. Oladunni
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Jun-Gyu Park
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Paula Pino Tamayo
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Olga Gonzalez
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Anwari Akhter
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Anna Allué-Guardia
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Angélica Olmo-Fontánez
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
2Integrated Biomedical Sciences Program, University of Texas Health Science Center at San Antonio, TX, 78229, USA.
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Shalini Gautam
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Andreu Garcia-Vilanova
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Chengjin Ye
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Kevin Chiem
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
2Integrated Biomedical Sciences Program, University of Texas Health Science Center at San Antonio, TX, 78229, USA.
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Colwyn Headley
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Varun Dwivedi
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Laura M. Parodi
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Kendra J. Alfson
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Hilary M. Staples
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Alyssa Schami
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
2Integrated Biomedical Sciences Program, University of Texas Health Science Center at San Antonio, TX, 78229, USA.
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Juan I. Garcia
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Alison Whigham
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Roy Neal Platt II
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Michal Gazi
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Jesse Martinez
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Colin Chuba
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Stephanie Earley
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Oscar H Rodriguez
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Stephanie Davis Mdaki
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Katrina N Kavelish
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Renee Escalona
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Cory R. A. Hallam
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Corbett Christie
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Jean L. Patterson
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Tim J. C. Anderson
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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  • ORCID record for Tim J. C. Anderson
Ricardo Carrion Jr
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Edward J. Dick Jr
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Shannan Hall-Ursone
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Larry S. Schlesinger
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Deepak Kaushal
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Luis D. Giavedoni
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Xavier Alvarez
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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Joanne Turner
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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  • For correspondence: lmartinez@txbiomed.org jtorrelles@txbiomed.org joanneturner@txbiomed.org
Luis Martinez-Sobrido
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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  • For correspondence: lmartinez@txbiomed.org jtorrelles@txbiomed.org joanneturner@txbiomed.org
Jordi B. Torrelles
1Texas Biomedical Research Institute, San Antonio, TX, 78227, USA
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  • For correspondence: lmartinez@txbiomed.org jtorrelles@txbiomed.org joanneturner@txbiomed.org
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ABSTRACT

Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease currently lacks a validated small animal model. Here, we show that transgenic mice expressing human angiotensin converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2-transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2-transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 4. K18 hACE2-transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.

Competing Interest Statement

The authors have declared no competing interest.

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Lethality of SARS-CoV-2 infection in K18 human angiotensin converting enzyme 2 transgenic mice
Fatai S. Oladunni, Jun-Gyu Park, Paula Pino Tamayo, Olga Gonzalez, Anwari Akhter, Anna Allué-Guardia, Angélica Olmo-Fontánez, Shalini Gautam, Andreu Garcia-Vilanova, Chengjin Ye, Kevin Chiem, Colwyn Headley, Varun Dwivedi, Laura M. Parodi, Kendra J. Alfson, Hilary M. Staples, Alyssa Schami, Juan I. Garcia, Alison Whigham, Roy Neal Platt II, Michal Gazi, Jesse Martinez, Colin Chuba, Stephanie Earley, Oscar H Rodriguez, Stephanie Davis Mdaki, Katrina N Kavelish, Renee Escalona, Cory R. A. Hallam, Corbett Christie, Jean L. Patterson, Tim J. C. Anderson, Ricardo Carrion Jr, Edward J. Dick Jr, Shannan Hall-Ursone, Larry S. Schlesinger, Deepak Kaushal, Luis D. Giavedoni, Xavier Alvarez, Joanne Turner, Luis Martinez-Sobrido, Jordi B. Torrelles
bioRxiv 2020.07.18.210179; doi: https://doi.org/10.1101/2020.07.18.210179
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Lethality of SARS-CoV-2 infection in K18 human angiotensin converting enzyme 2 transgenic mice
Fatai S. Oladunni, Jun-Gyu Park, Paula Pino Tamayo, Olga Gonzalez, Anwari Akhter, Anna Allué-Guardia, Angélica Olmo-Fontánez, Shalini Gautam, Andreu Garcia-Vilanova, Chengjin Ye, Kevin Chiem, Colwyn Headley, Varun Dwivedi, Laura M. Parodi, Kendra J. Alfson, Hilary M. Staples, Alyssa Schami, Juan I. Garcia, Alison Whigham, Roy Neal Platt II, Michal Gazi, Jesse Martinez, Colin Chuba, Stephanie Earley, Oscar H Rodriguez, Stephanie Davis Mdaki, Katrina N Kavelish, Renee Escalona, Cory R. A. Hallam, Corbett Christie, Jean L. Patterson, Tim J. C. Anderson, Ricardo Carrion Jr, Edward J. Dick Jr, Shannan Hall-Ursone, Larry S. Schlesinger, Deepak Kaushal, Luis D. Giavedoni, Xavier Alvarez, Joanne Turner, Luis Martinez-Sobrido, Jordi B. Torrelles
bioRxiv 2020.07.18.210179; doi: https://doi.org/10.1101/2020.07.18.210179

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