High expression of interleukin-18 receptor alpha correlates with severe respiratory viral disease and defines T cells with reduced cytotoxic signatures

Aira F. Cabug, Jeremy Chase Crawford, Hayley A. McQuilten, Isabelle J. H. Foo, Lilith F. Allen, Deborah Gebregzabher, Robert C. Mettelman, Tanya Novak, Janet Chou, Louise C. Rowntree, Ruth R. Hagen, Abby J. Thomson, Genevieve E. Martin, Brad Gilbertson, Michael NT Souter, Fiona James, Emma Goodall, Simone Rizzetto, Tim Flerlage, Xiaoxiao Jia, Lee-Ann Van de Velde, So Young Chang, Fabio Luciani, Ryan S. Thwaites, Jason A. Trubiano, Tom C. Kotsimbos, Allen C. Cheng, Adrienne G. Randolph, Paul G. Thomas, Jianqing Xu, Zhongfang Wang, Thi H. O. Nguyen, Brendon Y. Chua, Lukasz Kedzierski and Katherine Kedzierska ()
Additional contact information
Aira F. Cabug: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Jeremy Chase Crawford: St. Jude Children’s Research Hospital, Department of Host-Microbe Interactions
Hayley A. McQuilten: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Isabelle J. H. Foo: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Lilith F. Allen: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Deborah Gebregzabher: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Robert C. Mettelman: St. Jude Children’s Research Hospital, Department of Host-Microbe Interactions
Tanya Novak: Harvard Medical School, Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children’s Hospital and Department of Anaesthesia
Janet Chou: Harvard Medical School, Division of Immunology, Boston Children’s Hospital
Louise C. Rowntree: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Ruth R. Hagen: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Abby J. Thomson: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Genevieve E. Martin: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Brad Gilbertson: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Michael NT Souter: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Fiona James: Austin Health, Department of Infectious Diseases
Emma Goodall: Austin Health, Department of Infectious Diseases
Simone Rizzetto: UNSW Sydney, School of Medical Sciences and The Kirby Institute
Tim Flerlage: The University of Tennessee Health Science Center, Department of Pediatrics
Xiaoxiao Jia: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Lee-Ann Van de Velde: St. Jude Children’s Research Hospital, Department of Host-Microbe Interactions
So Young Chang: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Fabio Luciani: UNSW Sydney, School of Medical Sciences and The Kirby Institute
Ryan S. Thwaites: Imperial College London, National Heart and Lung Institute
Jason A. Trubiano: Peter MacCallum Cancer Centre, Department of Infectious Diseases
Tom C. Kotsimbos: The Alfred Hospital, Department of Respiratory Medicine
Allen C. Cheng: Monash University, School of Public Health and Preventive Medicine
Adrienne G. Randolph: Harvard Medical School, Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children’s Hospital and Department of Anaesthesia
Paul G. Thomas: St. Jude Children’s Research Hospital, Department of Host-Microbe Interactions
Jianqing Xu: Fudan University, Shanghai Public Health Clinical Centre and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Medical College
Zhongfang Wang: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Thi H. O. Nguyen: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Brendon Y. Chua: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Lukasz Kedzierski: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne
Katherine Kedzierska: at the Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne

Nature Communications, 2025, vol. 16, issue 1, 1-19

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.

Date: 2025
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DOI: 10.1038/s41467-025-65262-5

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