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; Berthold Göttgens; Mark Toshner; Christoph Hess; John R. Bradley; Paul A. Lyons; Kenneth G.C. Smith; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration

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

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 HosmilloKelvin 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, Berthold Göttgens, Mark Toshner, Christoph Hess, John R. Bradley, Paul A. Lyons, Kenneth G.C. Smith, Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration

Research output: Contribution to journal › Article › Research › peer-review

236 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1257-1275.e8
Number of pages	28
Journal	Immunity
Volume	54
Issue number	6
DOIs	https://doi.org/10.1016/j.immuni.2021.05.010
Publication status	Published - 8 Jun 2021
Externally published	Yes

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.immuni.2021.05.010Licence: CC BY

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Bergamaschi, L., Mescia, F., Turner, L., Hanson, A. L., Kotagiri, P., Dunmore, B. J., Ruffieux, H., de Sa, A., Huhn, O., Morgan, M. D., Gerber, P. P., Wills, M. R., Baker, S., Calero-Nieto, F. J., Doffinger, R., Dougan, G., Elmer, A., Goodfellow, I. G., Gupta, R. K., ... Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration (2021). Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease. Immunity, 54(6), 1257-1275.e8. https://doi.org/10.1016/j.immuni.2021.05.010

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

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 = "bystander CD8+ T cell, complement, COVID-19, immune pathology, interferon, recovery, SARS-CoV-2, systemic inflammation, TNF-α",

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note = "Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = jun,

day = "8",

doi = "10.1016/j.immuni.2021.05.010",

language = "English",

volume = "54",

pages = "1257--1275.e8",

journal = "Immunity",

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Bergamaschi, L, Mescia, F, Turner, L, Hanson, AL, Kotagiri, P, Dunmore, BJ, Ruffieux, H, de Sa, A, Huhn, O, Morgan, MD, Gerber, PP, Wills, MR, Baker, S, Calero-Nieto, FJ, Doffinger, R, Dougan, G, Elmer, A, Goodfellow, IG, Gupta, RK, Hosmillo, M, Hunter, K, Kingston, N, Lehner, PJ, Matheson, NJ, Nicholson, JK, Petrunkina, AM, Richardson, S, Saunders, C, Thaventhiran, JED, Toonen, EJM, Weekes, MP, Göttgens, B, Toshner, M, Hess, C, Bradley, JR, Lyons, PA, Smith, KGC & Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration 2021, 'Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease', Immunity, vol. 54, no. 6, pp. 1257-1275.e8. https://doi.org/10.1016/j.immuni.2021.05.010

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 - de Sa, Aloka

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.

AU - Allison, John

AU - Ansaripour, Ali

AU - Betancourt, Ariana

AU - Bong, Sze How

AU - Bower, Georgie

AU - Bucke, Ashlea

AU - Bullman, Ben

AU - Bunclark, Katherine

AU - Butcher, Helen

AU - Calder, Jo

AU - Canna, Laura

AU - Caputo, Daniela

AU - Clapham-Riley, Debbie

AU - Cossetti, Chiara

AU - Coudert, Jerome D.

AU - de Bie, Eckart M.D.D.

AU - Dewhurst, Eleanor

AU - di Stefano, Giovanni

AU - Domingo, Jason

AU - Epping, Madeline

AU - Fahey, Codie

AU - Fawke, Stuart

AU - Fuller, Stewart

AU - Furlong, Anita

AU - Gleadall, Nick

AU - Graf, Stefan

AU - Graves, Barbara

AU - Gray, Jennifer

AU - Grenfell, Richard

AU - Harris, Julie

AU - Hewitt, Sarah

AU - Hinch, Andrew

AU - Hodgson, Josh

AU - Holmes, Elaine

AU - Huang, Christopher

AU - Ivers, Tasmin

AU - Jackson, Sarah

AU - Jarvis, Isobel

AU - Jones, Emma

AU - Kennet, Jane

AU - Jose, Sherly

AU - Josipovic, Masa

AU - Kasanicki, Mary

AU - Kourampa, Jenny

AU - Laurenti, Elisa

AU - Legchenko, Ekaterina

AU - Le Gresley, Emma

AU - Lewis, Daniel

AU - Linger, Rachel

AU - Lyons, Paul A.

AU - Mackay, Michael

AU - Marioni, John C.

AU - Marsden, Jimmy

AU - Martin, Jennifer

AU - Matara, Cecilia

AU - Meadows, Anne

AU - Meloy, Sarah

AU - Mende, Nicole

AU - Michael, Alice

AU - Michel, Rachel

AU - Mwaura, Lucy

AU - Muldoon, Francesca

AU - Nice, Francesca

AU - O’Brien, Criona

AU - O’Donnell, Ciara

AU - Okecha, Georgina

AU - Omarjee, Ommar

AU - Ovington, Nigel

AU - Owehand, Willem H.

AU - Papadia, Sofia

AU - Patterson, Caroline

AU - Perera, Marianne

AU - Phelan, Isabel

AU - Pointon, Linda

AU - Polgarova, Petra

AU - Polwarth, Gary

AU - Pond, Nicole

AU - Price, Jane

AU - Publico, Cherry

AU - Rastall, Rebecca

AU - Ribeiro, Carla

AU - Richoz, Nathan

AU - Romashova, Veronika

AU - Rossi, Sabrina

AU - Rowlands, Jane

AU - Ruffolo, Valentina

AU - Yarkoni, Natalia Savinykh

AU - Sharma, Rahul

AU - Shih, Joy

AU - Selvan, Mayurun

AU - Spencer, Sarah

AU - Stefanucci, Luca

AU - Stark, Hannah

AU - Stephens, Jonathan

AU - Stirrups, Kathleen E.

AU - Strezlecki, Mateusz

AU - Summers, Charlotte

AU - Sutcliffe, Rachel

AU - Tilly, Tobias

AU - Tong, Zhen

AU - Tordesillas, Hugo

AU - Treacy, Carmen

AU - Townsend, Paul

AU - Walker, Neil

AU - Webster, Jennifer

AU - Wilson, Nicola K.

AU - Wood, Jennifer

AU - Wylot, Marta

AU - Yong, Cissy

AU - Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration

PY - 2021/6/8

Y1 - 2021/6/8

N2 - 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.

AB - 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.

KW - bystander CD8+ T cell

KW - complement

KW - COVID-19

KW - immune pathology

KW - interferon

KW - recovery

KW - SARS-CoV-2

KW - systemic inflammation

KW - TNF-α

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U2 - 10.1016/j.immuni.2021.05.010

DO - 10.1016/j.immuni.2021.05.010

M3 - Article

C2 - 34051148

AN - SCOPUS:85107023094

SN - 1074-7613

VL - 54

SP - 1257-1275.e8

JO - Immunity

JF - Immunity

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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