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, A Thomson, Geneviève Martin, Brad Gilbertson, Michael N. T. Souter, Fiona James, Emma C Goodall, Simone Rizzetto, Tim Flerlage, Xiaoxiao Jia, Lee-Ann Van de Velde, So Young Chang, Fabio Luciani, Ryan S. Thwaites, Jason A. Trubiano, Tom Kotsimbos, Allen Cheng, Adrienne G. Randolph, Paul G. Thomas, Jianqing Xu, Zhongfang Wang, Thi H. O. Nguyen, Brendon Y. Chua, Łukasz Kedzierski, Katherine Kedzierska
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.