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 and Michael P. Gantier ()
Additional contact information
Tomalika R. Ullah: Hudson Institute of Medical Research
Matt D. Johansen: Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences
Katherine R. Balka: Monash Biomedicine Discovery Institute, Monash University
Rebecca L. Ambrose: Hudson Institute of Medical Research
Linden J. Gearing: 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: Hudson Institute of Medical Research
W. Samantha N. Jayasekara: Hudson Institute of Medical Research
Daniel S. Wenholz: Noxopharm Limited
Vina R. Aldilla: UNSW Sydney
Jun Zeng: MedChemSoft Solutions
Stefan Miemczyk: Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences
Duc H. Nguyen: Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences
Nicole G. Hansbro: Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences
Rajan Venkatraman: Monash Biomedicine Discovery Institute, Monash University
Jung Hee Kang: Monash Biomedicine Discovery Institute, Monash University
Ee Shan Pang: Monash Biomedicine Discovery Institute, Monash University
Belinda J. Thomas: Hudson Institute of Medical Research
Arwaf S. Alharbi: Hudson Institute of Medical Research
Refaya Rezwan: Hudson Institute of Medical Research
Meredith O’Keeffe: Monash Biomedicine Discovery Institute, Monash University
William A. Donald: UNSW Sydney
Julia I. Ellyard: Australian National University
Wilson Wong: Hudson Institute of Medical Research
Naresh Kumar: UNSW Sydney
Benjamin T. Kile: Monash Biomedicine Discovery Institute, Monash University
Carola G. Vinuesa: Australian National University
Graham E. Kelly: Noxopharm Limited
Olivier F. Laczka: Noxopharm Limited
Philip M. Hansbro: Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences
Dominic De Nardo: Monash Biomedicine Discovery Institute, Monash University
Michael P. Gantier: Hudson Institute of Medical Research

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-41381-9

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