Shared neutrophil and T cell dysfunction is accompanied by a distinct interferon signature during severe febrile illnesses in children

Harsita Patel, Michael J. Carter, Heather Jackson, Oliver Powell, Matthew Fish, Manuela Terranova-Barberio, Filomena Spada, Nedyalko Petrov, Paul Wellman, Sarah Darnell, Sobia Mustafa, Katrina Todd, Cynthia Bishop, Jonathan M. Cohen, Julia Kenny, Sarah Berg, Thomas Sun, Francesca Davis, Aislinn Jennings, Emma Timms, Jessica Thomas, Maggie Nyirendra, Samuel Nichols, Leire Estamiana Elorieta, Giselle D’Souza, Victoria Wright, Tisham De, Dominic Habgood-Coote, Padmanabhan Ramnarayan, Pierre Tissières, Elizabeth Whittaker, Jethro Herberg, Aubrey Cunnington, Myrsini Kaforou, Richard Ellis, Michael H. Malim, Shane M. Tibby, Manu Shankar-Hari () and Michael Levin ()
Additional contact information
Harsita Patel: Imperial College London
Michael J. Carter: St Thomas’ Hospital
Heather Jackson: Imperial College London
Oliver Powell: Imperial College London
Matthew Fish: Great Maze Pond
Manuela Terranova-Barberio: Great Maze Pond
Filomena Spada: Great Maze Pond
Nedyalko Petrov: Great Maze Pond
Paul Wellman: Guy’s and St Thomas’ NHS Foundation Trust
Sarah Darnell: Imperial College London
Sobia Mustafa: Imperial College London
Katrina Todd: Great Maze Pond
Cynthia Bishop: Great Maze Pond
Jonathan M. Cohen: Evelina London Children’s Hospital
Julia Kenny: Evelina London Children’s Hospital
Sarah Berg: Guy’s and St Thomas’ NHS Foundation Trust
Thomas Sun: Guy’s and St Thomas’ NHS Foundation Trust
Francesca Davis: Evelina London Children’s Hospital
Aislinn Jennings: St Thomas’ Hospital
Emma Timms: Great Maze Pond
Jessica Thomas: Lewisham and Greenwich NHS Foundation Trust
Maggie Nyirendra: Lewisham and Greenwich NHS Foundation Trust
Samuel Nichols: Imperial College London
Leire Estamiana Elorieta: Imperial College London
Giselle D’Souza: Imperial College London
Victoria Wright: Imperial College London
Tisham De: Imperial College London
Dominic Habgood-Coote: Imperial College London
Padmanabhan Ramnarayan: Imperial College London
Pierre Tissières: Departement de l’Essone
Elizabeth Whittaker: Imperial College London
Jethro Herberg: Imperial College London
Aubrey Cunnington: Imperial College London
Myrsini Kaforou: Imperial College London
Richard Ellis: Great Maze Pond
Michael H. Malim: Great Maze Pond
Shane M. Tibby: St Thomas’ Hospital
Manu Shankar-Hari: Little France Crescent
Michael Levin: Imperial College London

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Severe febrile illnesses in children encompass life-threatening organ dysfunction caused by diverse pathogens and other severe inflammatory syndromes. A comparative approach to these illnesses may identify shared and distinct features of host immune dysfunction amenable to immunomodulation. Here, using immunophenotyping with mass cytometry and cell stimulation experiments, we illustrate trajectories of immune dysfunction in 74 children with multi-system inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2, 30 with bacterial infection, 16 with viral infection, 8 with Kawasaki disease, and 42 controls. We explore these findings in a secondary cohort of 500 children with these illnesses and 134 controls. We show that neutrophil activation and apoptosis are prominent in multi-system inflammatory syndrome, and that this is partially shared with bacterial infection. We show that memory T cells from patients with multi-system inflammatory syndrome and bacterial infection are exhausted. In contrast, we show viral infection to be characterized by a distinct signature of decreased interferon signaling and lower interferon receptor gene expression. Improved understanding of immune dysfunction may improve approaches to immunomodulator therapy in severe febrile illnesses in children.

Date: 2024
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DOI: 10.1038/s41467-024-52246-0

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