Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months

Marianna Santopaolo; Michaela Gregorova; Fergus W Hamilton; David T Arnold; Anna E Long; Aurora Lacey; Alice Halliday; Holly E Baum; Kristy Hamilton; Rachel Milligan; Elizabeth H Oliver; Olivia E Pearce; Lea Knezevic; M B Morales-Aza; Alice J Milne; Emily J Milodowski; Eben Jones; Rajeka Lazarus; Anu Goenka; Adam H R Finn; Nick A Maskell; Andrew D Davidson; Kathleen M Gillespie; Linda Wooldridge; Laura Rivino

doi:10.1101/2022.11.25.22282759

Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months

Marianna Santopaolo, Michaela Gregorova, Fergus W Hamilton, David T Arnold, Anna E Long, Aurora Lacey, Alice Halliday, Holly E Baum, Kristy Hamilton, Rachel Milligan, Elizabeth H Oliver, Olivia E Pearce, Lea Knezevic, M B Morales-Aza, Alice J Milne, Emily J Milodowski, Eben Jones, Rajeka Lazarus, Anu Goenka, Adam H R FinnNick A Maskell, Andrew D Davidson, Kathleen M Gillespie, Linda Wooldridge, Laura Rivino^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

28 Citations (Scopus)

Abstract

COVID-19 causes immune perturbations which may persist long-term, and patients frequently report ongoing symptoms for months after recovery. We assessed immune activation at 3-12 months post hospital admission in 187 samples from 63 patients with mild, moderate or severe disease and investigated whether it associates with long COVID. At 3 months, patients with severe disease displayed persistent activation of CD4+ and CD8+ T-cells, based on expression of HLA-DR, CD38, Ki67 and granzyme B, and elevated plasma levels of IL-4, IL-7, IL-17 and TNF-α compared to mild and/or moderate patients. Plasma from severe patients at 3 months caused T-cells from healthy donors to upregulate IL-15Rα, suggesting that plasma factors in severe patients may increase T-cell responsiveness to IL-15-driven bystander activation. Patients with severe disease reported a higher number of long COVID symptoms which did not however, correlate with cellular immune activation/pro-inflammatory cytokines after adjusting for age, sex and disease severity. Our data suggests that long COVID and persistent immune activation may correlate independently with severe disease.

Original language	English
Article number	e85009
Journal	eLife
Volume	12
Early online date	13 Jun 2023
DOIs	https://doi.org/10.1101/2022.11.25.22282759 https://doi.org/10.7554/eLife.85009
Publication status	E-pub ahead of print - 13 Jun 2023

Bibliographical note

Funding Information:
are grateful to all patients and their families for participating in this study 堀 This work was supported by

Publisher Copyright:
© 2023, eLife Sciences Publications Ltd. All rights reserved.

Research Groups and Themes

Academic Respiratory Unit

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Santopaolo, M., Gregorova, M., Hamilton, F. W., Arnold, D. T., Long, A. E., Lacey, A., Halliday, A., Baum, H. E., Hamilton, K., Milligan, R., Oliver, E. H., Pearce, O. E., Knezevic, L., Morales-Aza, M. B., Milne, A. J., Milodowski, E. J., Jones, E., Lazarus, R., Goenka, A., ... Rivino, L. (2023). Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months. eLife, 12, Article e85009. Advance online publication. https://doi.org/10.1101/2022.11.25.22282759, https://doi.org/10.7554/eLife.85009

@article{0deb8b269a7646639f1d40706175dbc4,

title = "Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months",

abstract = "COVID-19 causes immune perturbations which may persist long-term, and patients frequently report ongoing symptoms for months after recovery. We assessed immune activation at 3-12 months post hospital admission in 187 samples from 63 patients with mild, moderate or severe disease and investigated whether it associates with long COVID. At 3 months, patients with severe disease displayed persistent activation of CD4+ and CD8+ T-cells, based on expression of HLA-DR, CD38, Ki67 and granzyme B, and elevated plasma levels of IL-4, IL-7, IL-17 and TNF-α compared to mild and/or moderate patients. Plasma from severe patients at 3 months caused T-cells from healthy donors to upregulate IL-15Rα, suggesting that plasma factors in severe patients may increase T-cell responsiveness to IL-15-driven bystander activation. Patients with severe disease reported a higher number of long COVID symptoms which did not however, correlate with cellular immune activation/pro-inflammatory cytokines after adjusting for age, sex and disease severity. Our data suggests that long COVID and persistent immune activation may correlate independently with severe disease.",

author = "Marianna Santopaolo and Michaela Gregorova and Hamilton, {Fergus W} and Arnold, {David T} and Long, {Anna E} and Aurora Lacey and Alice Halliday and Baum, {Holly E} and Kristy Hamilton and Rachel Milligan and Oliver, {Elizabeth H} and Pearce, {Olivia E} and Lea Knezevic and Morales-Aza, {M B} and Milne, {Alice J} and Milodowski, {Emily J} and Eben Jones and Rajeka Lazarus and Anu Goenka and Finn, {Adam H R} and Maskell, {Nick A} and Davidson, {Andrew D} and Gillespie, {Kathleen M} and Linda Wooldridge and Laura Rivino",

note = "Funding Information: are grateful to all patients and their families for participating in this study 堀 This work was supported by Publisher Copyright: {\textcopyright} 2023, eLife Sciences Publications Ltd. All rights reserved.",

year = "2023",

month = jun,

day = "13",

doi = "10.1101/2022.11.25.22282759",

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Santopaolo, M, Gregorova, M, Hamilton, FW , Arnold, DT , Long, AE, Lacey, A, Halliday, A, Baum, HE, Hamilton, K, Milligan, R, Oliver, EH, Pearce, OE, Knezevic, L, Morales-Aza, MB , Milne, AJ , Milodowski, EJ, Jones, E, Lazarus, R , Goenka, A , Finn, AHR , Maskell, NA , Davidson, AD , Gillespie, KM , Wooldridge, L & Rivino, L 2023, 'Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months', eLife, vol. 12, e85009. https://doi.org/10.1101/2022.11.25.22282759, https://doi.org/10.7554/eLife.85009

TY - JOUR

T1 - Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months

AU - Santopaolo, Marianna

AU - Gregorova, Michaela

AU - Hamilton, Fergus W

AU - Arnold, David T

AU - Long, Anna E

AU - Lacey, Aurora

AU - Halliday, Alice

AU - Baum, Holly E

AU - Hamilton, Kristy

AU - Milligan, Rachel

AU - Oliver, Elizabeth H

AU - Pearce, Olivia E

AU - Knezevic, Lea

AU - Morales-Aza, M B

AU - Milne, Alice J

AU - Milodowski, Emily J

AU - Jones, Eben

AU - Lazarus, Rajeka

AU - Goenka, Anu

AU - Finn, Adam H R

AU - Maskell, Nick A

AU - Davidson, Andrew D

AU - Gillespie, Kathleen M

AU - Wooldridge, Linda

AU - Rivino, Laura

N1 - Funding Information: are grateful to all patients and their families for participating in this study 堀 This work was supported by Publisher Copyright: © 2023, eLife Sciences Publications Ltd. All rights reserved.

PY - 2023/6/13

Y1 - 2023/6/13

N2 - COVID-19 causes immune perturbations which may persist long-term, and patients frequently report ongoing symptoms for months after recovery. We assessed immune activation at 3-12 months post hospital admission in 187 samples from 63 patients with mild, moderate or severe disease and investigated whether it associates with long COVID. At 3 months, patients with severe disease displayed persistent activation of CD4+ and CD8+ T-cells, based on expression of HLA-DR, CD38, Ki67 and granzyme B, and elevated plasma levels of IL-4, IL-7, IL-17 and TNF-α compared to mild and/or moderate patients. Plasma from severe patients at 3 months caused T-cells from healthy donors to upregulate IL-15Rα, suggesting that plasma factors in severe patients may increase T-cell responsiveness to IL-15-driven bystander activation. Patients with severe disease reported a higher number of long COVID symptoms which did not however, correlate with cellular immune activation/pro-inflammatory cytokines after adjusting for age, sex and disease severity. Our data suggests that long COVID and persistent immune activation may correlate independently with severe disease.

AB - COVID-19 causes immune perturbations which may persist long-term, and patients frequently report ongoing symptoms for months after recovery. We assessed immune activation at 3-12 months post hospital admission in 187 samples from 63 patients with mild, moderate or severe disease and investigated whether it associates with long COVID. At 3 months, patients with severe disease displayed persistent activation of CD4+ and CD8+ T-cells, based on expression of HLA-DR, CD38, Ki67 and granzyme B, and elevated plasma levels of IL-4, IL-7, IL-17 and TNF-α compared to mild and/or moderate patients. Plasma from severe patients at 3 months caused T-cells from healthy donors to upregulate IL-15Rα, suggesting that plasma factors in severe patients may increase T-cell responsiveness to IL-15-driven bystander activation. Patients with severe disease reported a higher number of long COVID symptoms which did not however, correlate with cellular immune activation/pro-inflammatory cytokines after adjusting for age, sex and disease severity. Our data suggests that long COVID and persistent immune activation may correlate independently with severe disease.

U2 - 10.1101/2022.11.25.22282759

DO - 10.1101/2022.11.25.22282759

M3 - Article (Academic Journal)

C2 - 37310006

SN - 2050-084X

VL - 12

JO - eLife

JF - eLife

M1 - e85009

ER -

Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months

Abstract

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