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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
Volume 15 - 2024 |
doi: 10.3389/fimmu.2024.1440324
This article is part of the Research Topic Immune studies of SARS-CoV2 and vaccines using preclinical modeling View all 9 articles
Pulmonary SARS-CoV-2 infection leads to para-infectious immune activation in the brain
Provisionally accepted
Cordelia Dunai
1,2*
Claire Heatherington
3
Sarah A. Boardman
3*
Jordan Clark
4,5,6*
Parul Sharma
6*
Krishanthi Subramaniam
6
Kukatharmini Tharmaratnam
7*
Edward Needham
8
Robyn Williams
9
Andrew Fower
9*
Hannah Fox
9
Yun Huang
2*
Greta K. Wood
2*
Ceryce Collie
2
Mark A. Ellul
2*
Marie Held
10
Franklyn N. Egbe
2*
MIchael J. Griffiths
2
Tom Solomon
1,11,2
Gerome Breen
12,13*
Anja Kipar
14
Jonathan Cavanagh
15
Sarosh Irani
16,9*
Angela Vincent
9
James P. Stewart
6
Leonie Taams
17
David K. Menon
18*
Benedict D. Michael
1,11,2*- 1 NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, North West England, United Kingdom
- 2 Clinical Infection Microbiology and Immunology, Institute of Infection Ecology and Veterinary Sciences, University of Liverpool, Liverpool, United Kingdom
- 3 Clinical Infection, Microbiology, and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
- 4 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- 5 Center for Vaccine Research and Pandemic Preparedness, Icahn School of Medicine at Mount Sinai, New York, New York, United States
- 6 Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
- 7 Department of Health Data Science, Institute of Population Health, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, North West England, United Kingdom
- 8 Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
- 9 Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
- 10 Centre for Cell Imaging, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
- 11 The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom
- 12 Department of Social, Genetic & Developmental Psychiatry Centre, School of Mental Health & Psychological Sciences, King's College London, London, England, United Kingdom
- 13 NIHR Maudsley Biomedical Research Centre, King's College London, London, United Kingdom
- 14 Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
- 15 College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom
- 16 Mayo Clinic Florida, Jacksonville, Florida, United States
- 17 Centre for Inflammation Biology and Cancer Immunology, Department of Immunobiology, Faculty of Life Sciences & Medicine, King's College London, London, England, United Kingdom
- 18 Division of Anaesthesia, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom
Neurological complications, including encephalopathy and stroke, occur in a significant proportion of COVID-19 cases but viral protein is seldom detected in the brain parenchyma. To model this situation, we developed a novel low-inoculum K18-hACE2 mouse model of SARS-CoV-2 infection during which active viral replication was consistently seen in mouse lungs but not in the brain. We found that several mediators previously associated with encephalopathy in clinical samples were upregulated in the lung, including CCL2, and IL-6. In addition, several inflammatory mediations, including CCL4, IFNγ, IL-17A, were upregulated in the brain, associated with microglial reactivity. Parallel, in vitro experiments demonstrated that the filtered supernatant from SARS-CoV-2 virion exposed brain endothelial cells induced activation of uninfected microglia. This model successfully recreates SARS-CoV-2 virus-associated parainfectious brain inflammation which can be used to study the pathophysiology of the human neurological complications and the identification of potential immune targets for treatment.
Keywords: Virology, immunology, SARS-CoV-2, Neurology, Microglia
Received: 29 May 2024; Accepted: 04 Sep 2024.
Copyright: © 2024 Dunai, Heatherington, Boardman, Clark, Sharma, Subramaniam, Tharmaratnam, Needham, Williams, Fower, Fox, Huang, Wood, Collie, Ellul, Held, Egbe, Griffiths, Solomon, Breen, Kipar, Cavanagh, Irani, Vincent, Stewart, Taams, Menon and Michael. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Cordelia Dunai, NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, Liverpool, L69 3GL, North West England, United Kingdom
Sarah A. Boardman, Clinical Infection, Microbiology, and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
Jordan Clark, Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, United States
Parul Sharma, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
Kukatharmini Tharmaratnam, Department of Health Data Science, Institute of Population Health, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, L69 3GF, North West England, United Kingdom
Andrew Fower, Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
Yun Huang, Clinical Infection Microbiology and Immunology, Institute of Infection Ecology and Veterinary Sciences, University of Liverpool, Liverpool, United Kingdom
Greta K. Wood, Clinical Infection Microbiology and Immunology, Institute of Infection Ecology and Veterinary Sciences, University of Liverpool, Liverpool, United Kingdom
Mark A. Ellul, Clinical Infection Microbiology and Immunology, Institute of Infection Ecology and Veterinary Sciences, University of Liverpool, Liverpool, United Kingdom
Franklyn N. Egbe, Clinical Infection Microbiology and Immunology, Institute of Infection Ecology and Veterinary Sciences, University of Liverpool, Liverpool, United Kingdom
Gerome Breen, Department of Social, Genetic & Developmental Psychiatry Centre, School of Mental Health & Psychological Sciences, King's College London, London, WC2R 2LS, England, United Kingdom
Sarosh Irani, Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
David K. Menon, Division of Anaesthesia, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom
Benedict D. Michael, Clinical Infection Microbiology and Immunology, Institute of Infection Ecology and Veterinary Sciences, University of Liverpool, Liverpool, United Kingdom
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