Integrated immune dynamics define correlates of COVID-19 severity and antibody responses

Marios Koutsakos; Louise C Rowntree; Luca Hensen; Brendon Y Chua; Carolien E van de Sandt; Jennifer R Habel; Wuji Zhang; Xiaoxiao Jia; Lukasz Kedzierski; Thomas M Ashhurst; Givanna H Putri; Felix Marsh-Wakefield; Mark N Read; Davis N Edwards; E Bridie Clemens; Chinn Yi Wong; Francesca L Mordant; Jennifer A Juno; Fatima Amanat; Jennifer Audsley; Natasha E Holmes; Claire L Gordon; Olivia C Smibert; Jason A Trubiano; Carly M Hughes; Mike Catton; Justin T Denholm; Steven Y C Tong; Denise L Doolan; Tom C Kotsimbos; David C Jackson; Florian Krammer; Dale I Godfrey; Amy W Chung; Nicholas J C King; Sharon R Lewin; Adam K Wheatley; Stephen J Kent; Kanta Subbarao; James McMahon; Irani Thevarajan; Thi H O Nguyen; Allen C Cheng; Katherine Kedzierska

doi:10.1016/j.xcrm.2021.100208

Integrated immune dynamics define correlates of COVID-19 severity and antibody responses

Cell Rep Med. 2021 Mar 16;2(3):100208. doi: 10.1016/j.xcrm.2021.100208. Epub 2021 Feb 5.

Authors

Marios Koutsakos¹, Louise C Rowntree¹, Luca Hensen¹, Brendon Y Chua^{1

2}, Carolien E van de Sandt^{1

3}, Jennifer R Habel¹, Wuji Zhang¹, Xiaoxiao Jia¹, Lukasz Kedzierski^{1

4}, Thomas M Ashhurst^{5

6}, Givanna H Putri^{7

8}, Felix Marsh-Wakefield^{7

9

10}, Mark N Read^{7

8

11}, Davis N Edwards^{8

11}, E Bridie Clemens¹, Chinn Yi Wong¹, Francesca L Mordant¹, Jennifer A Juno¹, Fatima Amanat^{12

13}, Jennifer Audsley¹⁴, Natasha E Holmes^{15

16

17

18}, Claire L Gordon^{1

15}, Olivia C Smibert^{15

19

20}, Jason A Trubiano^{18

19

20

21}, Carly M Hughes²², Mike Catton²³, Justin T Denholm^{14

24}, Steven Y C Tong^{14

24

25}, Denise L Doolan²⁶, Tom C Kotsimbos^{27

28}, David C Jackson^{1

2}, Florian Krammer¹², Dale I Godfrey^{1

29}, Amy W Chung¹, Nicholas J C King^{5

6

7

9

30

31}, Sharon R Lewin^{14

24

32}, Adam K Wheatley^{1

33}, Stephen J Kent^{1

33

34}, Kanta Subbarao^{1

35}, James McMahon^{22

32}, Irani Thevarajan^{14

24}, Thi H O Nguyen¹, Allen C Cheng^{36

37}, Katherine Kedzierska^{1

2}

Affiliations

¹ Department of Microbiology and Immunology, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
² Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.
³ Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁴ Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Melbourne, VIC, Australia.
⁵ Sydney Cytometry Core Research Facility, Charles Perkins Centre, Centenary Institute and University of Sydney, Sydney, NSW, Australia.
⁶ Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, NSW, Australia.
⁷ Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.
⁸ School of Computer Science, University of Sydney, Sydney, NSW, Australia.
⁹ School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
¹⁰ Vascular Immunology Unit, Discipline of Pathology, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
¹¹ The Westmead Initiative, University of Sydney, Sydney, NSW, Australia.
¹² Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹³ Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
¹⁴ Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
¹⁵ Department of Infectious Diseases, Austin Hospital, Heidelberg, VIC, Australia.
¹⁶ Department of Medicine and Radiology, University of Melbourne, Parkville, VIC, Australia.
¹⁷ Data Analytics Research and Evaluation (DARE) Centre, Austin Health and University of Melbourne, Heidelberg, VIC, Australia.
¹⁸ Centre for Antibiotic Allergy and Research, Department of Infectious Diseases, Austin Health, Heidelberg, VIC, Australia.
¹⁹ Department of Infectious Diseases, Peter McCallum Cancer Centre, Melbourne, VIC, Australia.
²⁰ National Centre for Infections in Cancer, Peter McCallum Cancer Centre, Melbourne, VIC, Australia.
²¹ Department of Medicine (Austin Health), University of Melbourne, Heidelberg, VIC, Australia.
²² Monash Infectious Diseases, Monash Medical Centre, Monash Health, Melbourne, VIC, Australia.
²³ Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
²⁴ Victorian Infectious Diseases Services, Royal Melbourne Hospital and Doherty Department University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne VIC, Australia.
²⁵ Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia.
²⁶ Centre for Molecular Therapeutics, Australian Institute of Tropical Health & Medicine, James Cook University, Cairns, QLD, Australia.
²⁷ Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.
²⁸ Department of Allergy, Immunology, and Respiratory Medicine, Alfred Hospital, Melbourne, VIC, Australia.
²⁹ Australian Research Council Centre of Excellence for Advanced Molecular Imaging at the University of Melbourne, Melbourne, VIC, Australia.
³⁰ Viral Immunopathology Laboratory, Discipline of Pathology, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia.
³¹ Sydney Nano, University of Sydney, Sydney, NSW 2006, Australia.
³² Department of Infectious Diseases, Monash University and Alfred Hospital, Melbourne, VIC, Australia.
³³ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne, VIC, Australia.
³⁴ Melbourne Sexual Health Centre, Infectious Diseases Department, Alfred Health, Central Clinical School, Monash University, Melbourne, VIC, Australia.
³⁵ World Health Organization Collaborating Centre for Reference and Research on Influenza at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
³⁶ School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
³⁷ Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, VIC, Australia.

Abstract

SARS-CoV-2 causes a spectrum of COVID-19 disease, the immunological basis of which remains ill defined. We analyzed 85 SARS-CoV-2-infected individuals at acute and/or convalescent time points, up to 102 days after symptom onset, quantifying 184 immunological parameters. Acute COVID-19 presented with high levels of IL-6, IL-18, and IL-10 and broad activation marked by the upregulation of CD38 on innate and adaptive lymphocytes and myeloid cells. Importantly, activated CXCR3⁺cT_FH1 cells in acute COVID-19 significantly correlate with and predict antibody levels and their avidity at convalescence as well as acute neutralization activity. Strikingly, intensive care unit (ICU) patients with severe COVID-19 display higher levels of soluble IL-6, IL-6R, and IL-18, and hyperactivation of innate, adaptive, and myeloid compartments than patients with moderate disease. Our analyses provide a comprehensive map of longitudinal immunological responses in COVID-19 patients and integrate key cellular pathways of complex immune networks underpinning severe COVID-19, providing important insights into potential biomarkers and immunotherapies.

Keywords: CD38; HLA-DR; IL-18; IL-6; SARS-CoV-2; T follicular helper cells; acute COVID-19; antibody-secreting cells; convalescent COVID-19; soluble IL-6 receptor.

Publication types

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

MeSH terms

Adaptive Immunity
Adult
Aged
Antibodies, Viral / blood
Antibody Formation*
B-Lymphocytes / cytology
B-Lymphocytes / metabolism
COVID-19 / immunology*
COVID-19 / pathology
COVID-19 / virology
Female
Humans
Immunity, Innate
Interleukin-18 / metabolism
Interleukin-6 / metabolism
Male
Middle Aged
Receptors, CXCR3 / metabolism
Receptors, Interleukin-6 / metabolism
SARS-CoV-2 / immunology
SARS-CoV-2 / isolation & purification
Severity of Illness Index
Th1 Cells / cytology
Th1 Cells / metabolism
Young Adult

Substances

Antibodies, Viral
CXCR3 protein, human
Interleukin-18
Interleukin-6
Receptors, CXCR3
Receptors, Interleukin-6