High expression of interleukin-18 receptor alpha correlates with severe respiratory viral disease and defines T cells with reduced cytotoxic signatures
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.
Authors
- Brendon Y. Chua (ORCID: https://orcid.org/0000-0001-5654-1293)
- Fabio Luciani (ORCID: https://orcid.org/0000-0003-0666-6324)
- Tanya Novak (ORCID: https://orcid.org/0000-0002-7115-7545)
- Jianqing Xu (ORCID: https://orcid.org/0000-0003-0896-9273)
- Paul Glyndwr Thomas (ORCID: https://orcid.org/0000-0001-7955-0256)
- Katherine Kedzierska (ORCID: https://orcid.org/0000-0001-6141-335X)
- Aira F. Cabug
- Tim Flerlage
- Thi H. O. Nguyen (ORCID: https://orcid.org/0000-0002-9294-7693)
- Simone Rizzetto (ORCID: https://orcid.org/0000-0003-3881-8759)
- Łukasz Kedzierski (ORCID: https://orcid.org/0000-0003-0203-1057)
- Allen Cheng (ORCID: https://orcid.org/0000-0003-3152-116X)
- Janet Chou (ORCID: https://orcid.org/0000-0002-4610-2657)
- Lee-Ann Van de Velde (ORCID: https://orcid.org/0009-0000-6205-1151)
- So Young Chang (ORCID: https://orcid.org/0000-0002-6390-6462)
- Jason A. Trubiano (ORCID: https://orcid.org/0000-0002-5111-6367)
- Isabelle J. H. Foo (ORCID: https://orcid.org/0000-0002-4465-7245)
- Jeremy Chase Crawford (ORCID: https://orcid.org/0000-0003-4096-6048)
- Hayley A. McQuilten (ORCID: https://orcid.org/0000-0002-7089-5300)
- Fiona James (ORCID: https://orcid.org/0000-0003-0469-5666)
- Louise C. Rowntree (ORCID: https://orcid.org/0000-0002-0649-5089)
- A Thomson
- Ryan S. Thwaites (ORCID: https://orcid.org/0000-0003-3052-2793)
- Geneviève Martin (ORCID: https://orcid.org/0000-0001-5142-7440)
- Michael N. T. Souter (ORCID: https://orcid.org/0000-0002-1459-7923)
- Emma C Goodall (ORCID: https://orcid.org/0000-0001-5647-4123)
- Adrienne G. Randolph (ORCID: https://orcid.org/0000-0002-3084-3071)
- Robert C. Mettelman (ORCID: https://orcid.org/0000-0002-3527-5616)
- Ruth R. Hagen (ORCID: https://orcid.org/0000-0003-4437-2458)
- Brad Gilbertson (ORCID: https://orcid.org/0000-0001-7921-0032)
- Xiaoxiao Jia (ORCID: https://orcid.org/0000-0002-7833-468X)
- Deborah Gebregzabher (ORCID: https://orcid.org/0009-0001-0844-260X)
- Zhongfang Wang
- Tom Kotsimbos
- Lilith F. Allen (ORCID: https://orcid.org/0000-0002-4197-2573)
Institutions
- Boston Children's Hospital (US)
- St. Jude Children's Research Hospital (US)
- Shanghai Medical College of Fudan University (CN)
- Harvard University (US)
- University of Tennessee Health Science Center (US)
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- The Alfred Hospital (AU)
- UNSW Sydney (AU)
- First Affiliated Hospital of Guangzhou Medical University (CN)
- Peter Doherty Institute (AU)
- Monash Health (AU)
- Center for Pain and the Brain (US)
- State Key Laboratory of Respiratory Disease (CN)
- Austin Health (AU)
- Imperial College London (GB)
- Monash University (AU)
- Athens University of Economics and Business (GR)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1038/s41467-025-65262-5
- Citations
- 1
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- U.S. Department of Health and Human Services
- American Lebanese Syrian Associated Charities
- China Scholarship Council
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council
- National Institute of Allergy and Infectious Diseases