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Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19

Jordan J. Clark, Rebekah Penrice-Randal, Parul Sharma, Anja Kipar, Xiaofeng Dong, Andrew Davidson, Maia Kavanagh Williamson, View ORCID ProfileDavid A. Matthews, Lance Turtle, Tessa Prince, View ORCID ProfileGrant L. Hughes, Edward I. Patterson, Ghada Shawli, Krishanthi Subramaniam, Jo Sharp, Lynn McLaughlin, En-Min Zhou, Joseph D. Turner, Amy E. Marriott, Stefano Colombo, Shaun H. Pennington, Giancarlo Biagini, Andrew Owen, Julian A. Hiscox, View ORCID ProfileJames P. Stewart
doi: https://doi.org/10.1101/2020.10.13.334532
Jordan J. Clark
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
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Rebekah Penrice-Randal
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
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Parul Sharma
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
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Anja Kipar
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
2Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, University of Zurich, Switzerland
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Xiaofeng Dong
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
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Andrew Davidson
3School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, Bristol, UK
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Maia Kavanagh Williamson
3School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, Bristol, UK
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David A. Matthews
3School of Cellular and Molecular Medicine, Faculty of Life Sciences, University of Bristol, Bristol, UK
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  • ORCID record for David A. Matthews
Lance Turtle
4Department of Clinical Infection Microbiology and Immunology and NIHR Health Protection Research Unit for Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
5Tropical & Infectious Disease Unit, Royal Liverpool University Hospital
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Tessa Prince
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
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Grant L. Hughes
6Departments of Vector Biology and Tropical Disease Biology, Centre for Neglected Tropical Disease, Liverpool School of Tropical Medicine, Liverpool, UK
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Edward I. Patterson
6Departments of Vector Biology and Tropical Disease Biology, Centre for Neglected Tropical Disease, Liverpool School of Tropical Medicine, Liverpool, UK
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Ghada Shawli
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
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Krishanthi Subramaniam
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
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Jo Sharp
7Department of Pharmacology and Therapeutics, Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool, UK
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Lynn McLaughlin
8Biomedical Services Unit, University of Liverpool, UK
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En-Min Zhou
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
9Department of Preventive Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
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Joseph D. Turner
10Department of Tropical Disease Biology, Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, UK
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Amy E. Marriott
10Department of Tropical Disease Biology, Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, UK
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Stefano Colombo
10Department of Tropical Disease Biology, Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, UK
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Shaun H. Pennington
10Department of Tropical Disease Biology, Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, UK
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Giancarlo Biagini
10Department of Tropical Disease Biology, Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, UK
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Andrew Owen
7Department of Pharmacology and Therapeutics, Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool, UK
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Julian A. Hiscox
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
9Department of Preventive Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
11Infectious Diseases Horizontal Technology Centre (ID HTC), A*STAR, Singapore
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  • For correspondence: j.p.stewart@liv.ac.uk julian.hiscox@liverpool.ac.uk
James P. Stewart
1Department of Infection Biology & Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK
9Department of Preventive Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China
12Department of Infectious Disease, University of Georgia, Georgia, USA
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  • ORCID record for James P. Stewart
  • For correspondence: j.p.stewart@liv.ac.uk julian.hiscox@liverpool.ac.uk
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Abstract

COVID-19 is a spectrum of clinical symptoms in humans caused by infection with SARS-CoV-2, a recently emerged coronavirus that has rapidly caused a pandemic. Coalescence of a second wave of this virus with seasonal respiratory viruses, particularly influenza virus is a possible global health concern. To investigate this, transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) were first infected with IAV followed by SARS-CoV-2. The host response and effect on virus biology was compared to K18-hACE2 mice infected with IAV or SARS-CoV-2 only. Infection of mice with each individual virus resulted in a disease phenotype compared to control mice. Although SARS-CoV-2 RNA synthesis appeared significantly reduced in the sequentially infected mice, these mice had a more rapid weight loss, more severe lung damage and a prolongation of the innate response compared to singly infected or control mice. The sequential infection also exacerbated the extrapulmonary manifestations associated with SARS-CoV-2. This included a more severe encephalitis. Taken together, the data suggest that the concept of ‘twinfection’ is deleterious and mitigation steps should be instituted as part of a comprehensive public health response to the COVID-19 pandemic.

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 4.0 International license.
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Posted October 13, 2020.
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Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19
Jordan J. Clark, Rebekah Penrice-Randal, Parul Sharma, Anja Kipar, Xiaofeng Dong, Andrew Davidson, Maia Kavanagh Williamson, David A. Matthews, Lance Turtle, Tessa Prince, Grant L. Hughes, Edward I. Patterson, Ghada Shawli, Krishanthi Subramaniam, Jo Sharp, Lynn McLaughlin, En-Min Zhou, Joseph D. Turner, Amy E. Marriott, Stefano Colombo, Shaun H. Pennington, Giancarlo Biagini, Andrew Owen, Julian A. Hiscox, James P. Stewart
bioRxiv 2020.10.13.334532; doi: https://doi.org/10.1101/2020.10.13.334532
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Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19
Jordan J. Clark, Rebekah Penrice-Randal, Parul Sharma, Anja Kipar, Xiaofeng Dong, Andrew Davidson, Maia Kavanagh Williamson, David A. Matthews, Lance Turtle, Tessa Prince, Grant L. Hughes, Edward I. Patterson, Ghada Shawli, Krishanthi Subramaniam, Jo Sharp, Lynn McLaughlin, En-Min Zhou, Joseph D. Turner, Amy E. Marriott, Stefano Colombo, Shaun H. Pennington, Giancarlo Biagini, Andrew Owen, Julian A. Hiscox, James P. Stewart
bioRxiv 2020.10.13.334532; doi: https://doi.org/10.1101/2020.10.13.334532

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