Nature Communications (Sep 2023)
Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection
- Tomalika R. Ullah,
- Matt D. Johansen,
- Katherine R. Balka,
- Rebecca L. Ambrose,
- Linden J. Gearing,
- James Roest,
- Julian P. Vivian,
- Sunil Sapkota,
- W. Samantha N. Jayasekara,
- Daniel S. Wenholz,
- Vina R. Aldilla,
- Jun Zeng,
- Stefan Miemczyk,
- Duc H. Nguyen,
- Nicole G. Hansbro,
- Rajan Venkatraman,
- Jung Hee Kang,
- Ee Shan Pang,
- Belinda J. Thomas,
- Arwaf S. Alharbi,
- Refaya Rezwan,
- Meredith O’Keeffe,
- William A. Donald,
- Julia I. Ellyard,
- Wilson Wong,
- Naresh Kumar,
- Benjamin T. Kile,
- Carola G. Vinuesa,
- Graham E. Kelly,
- Olivier F. Laczka,
- Philip M. Hansbro,
- Dominic De Nardo,
- Michael P. Gantier
Affiliations
- Tomalika R. Ullah
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- Matt D. Johansen
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences
- Katherine R. Balka
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University
- Rebecca L. Ambrose
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- Linden J. Gearing
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- James Roest
- St. Vincent’s Institute of Medical Research
- Julian P. Vivian
- St. Vincent’s Institute of Medical Research
- Sunil Sapkota
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- W. Samantha N. Jayasekara
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- Daniel S. Wenholz
- Noxopharm Limited
- Vina R. Aldilla
- School of Chemistry, UNSW Sydney
- Jun Zeng
- MedChemSoft Solutions
- Stefan Miemczyk
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences
- Duc H. Nguyen
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences
- Nicole G. Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences
- Rajan Venkatraman
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University
- Jung Hee Kang
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University
- Ee Shan Pang
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University
- Belinda J. Thomas
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- Arwaf S. Alharbi
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- Refaya Rezwan
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- Meredith O’Keeffe
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University
- William A. Donald
- School of Chemistry, UNSW Sydney
- Julia I. Ellyard
- Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University
- Wilson Wong
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- Naresh Kumar
- School of Chemistry, UNSW Sydney
- Benjamin T. Kile
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University
- Carola G. Vinuesa
- Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University
- Graham E. Kelly
- Noxopharm Limited
- Olivier F. Laczka
- Noxopharm Limited
- Philip M. Hansbro
- Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences
- Dominic De Nardo
- Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University
- Michael P. Gantier
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research
- DOI
- https://doi.org/10.1038/s41467-023-41381-9
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 13
Abstract
Abstract TANK-binding kinase 1 (TBK1) is a key signalling component in the production of type-I interferons, which have essential antiviral activities, including against SARS-CoV-2. TBK1, and its homologue IκB kinase-ε (IKKε), can also induce pro-inflammatory responses that contribute to pathogen clearance. While initially protective, sustained engagement of type-I interferons is associated with damaging hyper-inflammation found in severe COVID-19 patients. The contribution of TBK1/IKKε signalling to these responses is unknown. Here we find that the small molecule idronoxil inhibits TBK1/IKKε signalling through destabilisation of TBK1/IKKε protein complexes. Treatment with idronoxil, or the small molecule inhibitor MRT67307, suppresses TBK1/IKKε signalling and attenuates cellular and molecular lung inflammation in SARS-CoV-2-challenged mice. Our findings additionally demonstrate that engagement of STING is not the major driver of these inflammatory responses and establish a critical role for TBK1/IKKε signalling in SARS-CoV-2 hyper-inflammation.
