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
- Katherine Kedzierska
2025-11-24
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.