Pulmonary SARS-CoV-2 infection leads to para-infectious immune activation in the brain
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 <i>in vitro</i> 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 para-infectious brain inflammation which can be used to study the pathophysiology of the neurological complications and the identification of potential immune targets for treatment.
Authors
- Greta K. Wood (ORCID: https://orcid.org/0000-0001-6098-2331)
- Franklyn Egbe (ORCID: https://orcid.org/0000-0002-9547-4609)
- Gerome D. Breen (ORCID: https://orcid.org/0000-0003-2053-1792)
- Tom Solomon (ORCID: https://orcid.org/0000-0001-7266-6547)
- Kukatharmini Tharmaratnam (ORCID: https://orcid.org/0000-0002-8255-9822)
- Mark Ellul (ORCID: https://orcid.org/0000-0002-6115-8245)
- Claire Hetherington (ORCID: https://orcid.org/0009-0003-9234-4459)
- Leonie S. Taams (ORCID: https://orcid.org/0000-0002-9337-7194)
- Marie Held (ORCID: https://orcid.org/0000-0003-0118-5898)
- Benedict Michael (ORCID: https://orcid.org/0000-0002-8693-8926)
- Edward Needham (ORCID: https://orcid.org/0000-0001-7042-7462)
- Sarosh R. Irani (ORCID: https://orcid.org/0000-0002-7667-9748)
- Jonathan Cavanagh (ORCID: https://orcid.org/0000-0003-0640-8050)
- Jordan J. Clark (ORCID: https://orcid.org/0000-0003-1790-7883)
- David Krishna Menon (ORCID: https://orcid.org/0000-0002-3228-9692)
- Andrew Fower (ORCID: https://orcid.org/0000-0003-0414-2367)
- Angela Vincent (ORCID: https://orcid.org/0000-0003-2395-8695)
- Anja Kipar (ORCID: https://orcid.org/0000-0001-7289-3459)
- Ceryce Collie (ORCID: https://orcid.org/0000-0002-0239-9401)
- Michael J. Griffiths (ORCID: https://orcid.org/0000-0003-1851-6155)
- Krishanthi Subramaniam (ORCID: https://orcid.org/0000-0002-1734-9351)
- Robyn Williams (ORCID: https://orcid.org/0000-0003-2099-0032)
- Cordelia Dunai (ORCID: https://orcid.org/0000-0001-5799-2387)
- Sarah A. Boardman
- Yun Huang (ORCID: https://orcid.org/0009-0004-8635-6063)
- Parul Sharma (ORCID: https://orcid.org/0000-0002-9090-7540)
- James P. Stewart
- Hannah Fox (ORCID: https://orcid.org/0000-0003-4667-4345)
Institutions
- University of Liverpool (GB)
- King's College London (GB)
- University of Zurich (CH)
- University of Cambridge (GB)
- Walton Centre (GB)
- University of Oxford (GB)
- NIHR Maudsley Dementia Biomedical Research Unit (GB)
- Centre for Inflammation Research (GB)
- Addenbrooke's Hospital (GB)
- Health Protection Research Unit in Emerging and Zoonotic Infections at University of Liverpool (GB)
- University of Glasgow (GB)
Publication Details
- Journal
- Frontiers in Immunology
- Published
- 2024-10-14
- DOI
- https://doi.org/10.3389/fimmu.2024.1440324
- Citations
- 3
- Primary Topic
- Long-Term Effects of COVID-19
- Type
- article
- Field-Weighted Citation Impact
- 1.11
Funders
- UK Research and Innovation
- National Institute for Health Research Health Protection Research Unit
- International Seafood Sustainability Foundation
- National Institute for Health and Care Research
- Imperial College London
- University of Oxford
- Public Health England
- Medical Research Council
- Biotechnology and Biological Sciences Research Council