TY - JOUR
T1 - Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease
AU - Bergamaschi, Laura
AU - Mescia, Federica
AU - Turner, Lorinda
AU - Hanson, Aimee L.
AU - Kotagiri, Prasanti
AU - Dunmore, Benjamin J.
AU - Ruffieux, Hélène
AU - Sa, Aloka De
AU - Huhn, Oisín
AU - Morgan, Michael D.
AU - Gerber, Pehuén Pereyra
AU - Wills, Mark R.
AU - Baker, Stephen
AU - Calero-Nieto, Fernando J.
AU - Doffinger, Rainer
AU - Dougan, Gordon
AU - Elmer, Anne
AU - Goodfellow, Ian G.
AU - Gupta, Ravindra K.
AU - Hosmillo, Myra
AU - Hunter, Kelvin
AU - Kingston, Nathalie
AU - Lehner, Paul J.
AU - Matheson, Nicholas J.
AU - Nicholson, Jeremy K.
AU - Petrunkina, Anna M.
AU - Richardson, Sylvia
AU - Saunders, Caroline
AU - Thaventhiran, James E.D.
AU - Toonen, Erik J.M.
AU - Weekes, Michael P.
AU - Göttgens, Berthold
AU - Toshner, Mark
AU - Hess, Christoph
AU - Bradley, John R.
AU - Lyons, Paul A.
AU - Smith, Kenneth G.C.
N1 - Acknowledgements
We thank all the patients and health care workers who consented to take part in this study. We are grateful to CVC Capital Partners, the Evelyn Trust (20/75), Addenbrooke's Charitable Trust, Cambridge University Hospitals (12/20A), the NIHR Cambridge Biomedical Research Centre, and the UKRI/NIHR through the UK Coronavirus Immunology Consortium (UK-CIC) for their financial support. Further support: K.G.C.S.: Wellcome Investigator Award (200871/Z/16/Z); M.P.W.: Wellcome Senior Clinical Research Fellowship (108070/Z/15/Z); C.H.: Wellcome COVID-19 Rapid Response DCF and the Fondation Botnar; N.M.: MRC (CSF MR/P008801/1), NHSBT (WPA15-02), and Addenbrooke's Charitable Trust, (grant ref. to 900239 NJM); I.G.G.: Wellcome Senior Fellowship and Wellcome grant (Ref: 207498/Z/17/Z); P.J.L.: Wellcome Trust Principal Research Fellowship (084957/Z/08/Z) and MRC (MR/V011561/1); J.K.N.: The Spinnaker Healthcare Research Trust and the McCusker Foundation as part of Australian National Phenome Centre. P.K. is the recipient of a Jacquot Research Entry Scholarship of the Royal Australasian College of Physicians Foundation. We would like to thank the NIHR Cambridge Clinical Research Facility outreach team for enrollment of patients; the NIHR Cambridge Biomedical Research Centre Cell Phenotyping Hub and the CRUK Cambridge Institute flow cytometry core facility for flow and mass cytometry; and the Cambridge NIHR BRC Stratified Medicine Core Laboratory NGS Hub (supported by an MRC Clinical Infrastructure Award) for RNA sequencing.
PY - 2021/6/8
Y1 - 2021/6/8
N2 - he 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.
AB - he 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.
UR - https://doi.org/10.1016/j.immuni.2021.05.010
U2 - 10.1016/j.immuni.2021.05.010
DO - 10.1016/j.immuni.2021.05.010
M3 - Article
VL - 54
SP - 1257-1275.e8
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 6
ER -