High expression of interleukin-18 receptor alpha correlates with severe respiratory viral disease and defines T cells with reduced cytotoxic signatures
Abstract
Abstract Hyperactivated immunity underpins severe outcomes of respiratory viral infections, yet specific immune perturbations are ill-defined. Our recent findings identified OLAH (oleoyl-ACP-hydrolase) as a driver of life-threatening viral diseases. In the same patient cohorts, we now identify the gene encoding IL-18Rα chain ( IL18R1 ), as being highly expressed in life-threatening influenza, COVID-19, RSV and multisystem inflammatory syndrome in children (MIS-C) and demonstrate markedly elevated surface protein IL-18Rα expression on CD8 T cells in these infections. Using a mouse model of severe influenza, we further show that high IL-18Rα expression on effector T cells is associated with increased disease severity. We find that IL-18Rα expression on CD8 T cells is inversely associated with cytotoxicity-related genes, including granzyme A, granzyme B, perforin, Eomes, and KLRG-1. Our study demonstrates that IL-18Rα is associated with severe and fatal respiratory disease outcomes and proposes the use of IL-18Rα as a potential biomarker for severe respiratory viral disease.
Article Details
Authors (35)
Aira F. Cabug
Jeremy Chase Crawford
Hayley A. McQuilten
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Isabelle J. H. Foo
Lilith F. Allen
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Deborah Gebregzabher
Robert C. Mettelman
Tanya Novak
Janet Chou
Louise C. Rowntree
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Ruth R. Hagen
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Abby J. Thomson
Genevieve E. Martin
Brad Gilbertson
Michael NT Souter
Fiona James
Emma Goodall
Simone Rizzetto
School of Biomedical Sciences, University of New South Wales
Tim Flerlage
Xiaoxiao Jia
Lee-Ann Van de Velde
So Young Chang
Fabio Luciani
School of Biomedical Sciences, University of New South Wales
Ryan S. Thwaites
National Heart and Lung Institute, Imperial College London
Jason A. Trubiano
Department of Infectious Diseases, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Tom C. Kotsimbos
Department of Respiratory Medicine, The Alfred Hospital
Allen C. Cheng
School of Public Health and Preventive Medicine, Monash University
Adrienne G. Randolph
Paul G. Thomas
Jianqing Xu
Shanghai Public Health Clinical Centre and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College, Fudan University
Zhongfang Wang
Thi H. O. Nguyen
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity
Brendon Y. Chua
Lukasz Kedzierski
Katherine Kedzierska
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity