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

doi:10.1038/s41467-023-41381-9

Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection

Nat Commun. 2023 Sep 18;14(1):5666. doi: 10.1038/s41467-023-41381-9.

Authors

Tomalika R Ullah^#^{1

2}, Matt D Johansen^#³, Katherine R Balka⁴, Rebecca L Ambrose^{1

2}, Linden J Gearing^{1

2}, James Roest⁵, Julian P Vivian^{5

6}, Sunil Sapkota^{1

2}, W Samantha N Jayasekara^{1

2}, Daniel S Wenholz^{7

8}, Vina R Aldilla⁸, Jun Zeng⁹, Stefan Miemczyk³, Duc H Nguyen³, Nicole G Hansbro³, Rajan Venkatraman⁴, Jung Hee Kang⁴, Ee Shan Pang⁴, Belinda J Thomas^{1

2

10}, Arwaf S Alharbi^{1

2

11}, Refaya Rezwan^{1

2}, Meredith O'Keeffe⁴, William A Donald⁸, Julia I Ellyard^{12

13}, Wilson Wong^{1

2

14}, Naresh Kumar⁸, Benjamin T Kile^{4

15}, Carola G Vinuesa^{12

13

16}, Graham E Kelly⁷, Olivier F Laczka⁷, Philip M Hansbro³, Dominic De Nardo⁴, Michael P Gantier^{17

18}

Affiliations

¹ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
² Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
³ Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia.
⁴ Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
⁵ St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
⁶ Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia.
⁷ Noxopharm Limited, Chatswood, NSW, Australia.
⁸ School of Chemistry, UNSW Sydney, Kensington, NSW, Australia.
⁹ MedChemSoft Solutions, Ferntree Gully, VIC, Australia.
¹⁰ Monash Lung and Sleep, Monash Medical Centre, Clayton, VIC, Australia.
¹¹ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Turabah, Saudi Arabia.
¹² Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
¹³ Centre for Personalised Immunology, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
¹⁴ Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia.
¹⁵ Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
¹⁶ Francis Crick Institute, London, UK.
¹⁷ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia. [email protected].
¹⁸ Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
COVID-19*
Disease Models, Animal
I-kappa B Kinase
Inflammation
Interferon Type I*
Mice
SARS-CoV-2

Substances

I-kappa B Kinase
Interferon Type I