Delayed bystander CD8 T cell activation, early immune pathology and persistent dysregulation characterise severe COVID-19

10.1101/2021.01.11.20248765

medRxiv

26th March 2021

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This research has not been peer-reviewed, and has been posted on pre-print repository medRxiv. This is a preliminary report that should not be regarded as conclusive, guide clinical practice/health-related behaviour, or be reported in news media as established information.


Abstract

In a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust bystander CD8 T cell immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed bystander responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune defects may have clinical implications.

Author list:

Affiliations

  1. Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
  2. Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
  3. MRC Biostatistics Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
  4. Cancer Research UK – Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK
  5. Department of Haematology, Wellcome & MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK
  6. Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
  7. Cambridge Clinical Research Centre, NIHR Clinical Research Facility, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
  8. Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
  9. Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
  10. NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  11. NHS Blood and Transplant, Cambridge, UK.
  12. The Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Murdoch, Western Australia WA 6150, Australia
  13. MRC Toxicology Unit, School of Biological Sciences, University of Cambridge, Cambridge CB2 1QR, UK
  14. R&D Department, Hycult Biotech, 5405 PD Uden, The Netherlands
  15. Heart and Lung Research Institute, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
  16. Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
  17. Department of Biomedicine, University and University Hospital Basel, 4031Basel, Switzerland
  18. Botnar Research Centre for Child Health (BRCCH) University Basel & ETH Zurich, 4058 Basel, Switzerland
  19. These authors contributed equally

* Corresponding authors

 

Authors

Laura Bergamaschi1, 2, 19, Federica Mescia1, 2, 19, Lorinda Turner1, 2, 19, Aimee Hanson1, 2, 19, Prasanti Kotagiri1, 2, 19, Benjamin J. Dunmore2, Hélène Ruffieux3, Aloka De Sa1, 2, Oisín Huhn2, Michael D Morgan4, 5, Pehuen Pereyra Gerber1, 2, Mark R. Wills1, 2, Stephen Baker1, 2, Fernando J Calero‐Nieto5, Rainer Doffinger6, Gordon Dougan1, 2, Anne Elmer7, Ian G Goodfellow8, Ravindra K. Gupta1, 2, Myra Hosmillo8, Kelvin Hunter1, 2, Nathalie Kingston9, 10, Paul J. Lehner1, 2, Nicholas J. Matheson1, 2,11, Jeremy K. Nicholson12, Anna M. Petrunkina1, 2, Sylvia Richardson3, Caroline Saunders7, James E.D. Thaventhiran1, 2, 13, Erik J. M. Toonen14, Michael P. Weekes1, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, Berthold Göttgens5, Mark Toshner2, 15, 16, Christoph Hess1, 2, 17, 18, John R. Bradley2,10, Paul A. Lyons* 1, 2, Kenneth G.C. Smith* 1, 2.