Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

Laura Bergamaschi; Federica Mescia; Lorinda Turner; Aimee L Hanson; Prasanti Kotagiri; Benjamin J Dunmore; Hélène Ruffieux; Aloka De Sa; Oisín Huhn; Michael D Morgan; Pehuén Pereyra Gerber; Mark R Wills; Stephen Baker; Fernando J Calero-Nieto; Rainer Doffinger; Gordon Dougan; Anne Elmer; Ian G Goodfellow; Ravindra K Gupta; Myra Hosmillo; Kelvin Hunter; Nathalie Kingston; Paul J Lehner; Nicholas J Matheson; Jeremy K Nicholson; Anna M Petrunkina; Sylvia Richardson; Caroline Saunders; James E D Thaventhiran; Erik J M Toonen; Michael P Weekes; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration; Berthold Göttgens; Mark Toshner; Christoph Hess; John R Bradley; Paul A Lyons; Kenneth G C Smith

doi:10.1016/j.immuni.2021.05.010

Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

Immunity. 2021 Jun 8;54(6):1257-1275.e8. doi: 10.1016/j.immuni.2021.05.010. Epub 2021 May 16.

Authors

Laura Bergamaschi¹, Federica Mescia¹, Lorinda Turner¹, Aimee L Hanson¹, Prasanti Kotagiri¹, Benjamin J Dunmore², Hélène Ruffieux³, Aloka De Sa¹, Oisín Huhn², Michael D Morgan⁴, Pehuén Pereyra Gerber¹, Mark R Wills¹, Stephen Baker¹, Fernando J Calero-Nieto⁵, Rainer Doffinger⁶, Gordon Dougan¹, Anne Elmer⁷, Ian G Goodfellow⁸, Ravindra K Gupta¹, Myra Hosmillo⁸, Kelvin Hunter¹, Nathalie Kingston⁹, Paul J Lehner¹, Nicholas J Matheson¹⁰, Jeremy K Nicholson¹¹, Anna M Petrunkina¹, Sylvia Richardson³, Caroline Saunders⁷, James E D Thaventhiran¹², Erik J M Toonen¹³, Michael P Weekes¹⁴; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration; Berthold Göttgens⁵, Mark Toshner¹⁵, Christoph Hess¹⁶, John R Bradley¹⁷, Paul A Lyons¹⁸, Kenneth G C Smith¹⁹

Affiliations

¹ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, 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 0SR, UK.
⁴ Cancer Research UK - Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, 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; NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
¹⁰ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK; NHS Blood and Transplant, Cambridge, UK.
¹¹ The Australian National Phenome Centre, Centre for Computational and Systems Medicine, Health Futures Institute, Murdoch University, Murdoch, Western Australia WA 6150, Australia.
¹² Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK; MRC Toxicology Unit, School of Biological Sciences, University of Cambridge, Cambridge CB2 1QR, UK.
¹³ R&D Department, Hycult Biotech, 5405 PD Uden, the Netherlands.
¹⁴ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
¹⁵ Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK; Heart and Lung Research Institute, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK; Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
¹⁶ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK; Department of Biomedicine, University and University Hospital Basel, 4031 Basel, Switzerland; Botnar Research Centre for Child Health (BRCCH) University Basel & ETH Zurich, 4058 Basel, Switzerland.
¹⁷ Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK; NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
¹⁸ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: pal34@cam.ac.uk.
¹⁹ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: kgcs2@cam.ac.uk.

Abstract

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8⁺ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications.

Keywords: COVID-19; SARS-CoV-2; TNF-α; bystander CD8+ T cell; complement; immune pathology; interferon; recovery; systemic inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
COVID-19 / diagnosis
COVID-19 / genetics
COVID-19 / immunology*
COVID-19 / virology*
Cytokines / metabolism
Disease Susceptibility
Gene Expression Profiling
Host-Pathogen Interactions / immunology*
Humans
Inflammation Mediators / metabolism
Longitudinal Studies
Lymphocyte Activation / genetics
Lymphocyte Activation / immunology*
Oxidative Phosphorylation
Phenotype
Prognosis
Reactive Oxygen Species / metabolism
SARS-CoV-2 / immunology*
Severity of Illness Index
Transcriptome

Substances

Biomarkers
Cytokines
Inflammation Mediators
Reactive Oxygen Species

Abstract

Publication types

MeSH terms

Substances

Grants and funding