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.
Tomalika R Ullah  #  1  2 ,  Matt D Johansen  #  3 ,  Katherine R Balka  4 ,  Rebecca L Ambrose  1  2 ,  Linden J Gearing  1  2 ,  James Roest  5 ,  Julian P Vivian  5  6 ,  Sunil Sapkota  1  2 ,  W Samantha N Jayasekara  1  2 ,  Daniel S Wenholz  7  8 ,  Vina R Aldilla  8 ,  Jun Zeng  9 ,  Stefan Miemczyk  3 ,  Duc H Nguyen  3 ,  Nicole G Hansbro  3 ,  Rajan Venkatraman  4 ,  Jung Hee Kang  4 ,  Ee Shan Pang  4 ,  Belinda J Thomas  1  2  10 ,  Arwaf S Alharbi  1  2  11 ,  Refaya Rezwan  1  2 ,  Meredith O'Keeffe  4 ,  William A Donald  8 ,  Julia I Ellyard  12  13 ,  Wilson Wong  1  2  14 ,  Naresh Kumar  8 ,  Benjamin T Kile  4  15 ,  Carola G Vinuesa  12  13  16 ,  Graham E Kelly  7 ,  Olivier F Laczka  7 ,  Philip M Hansbro  3 ,  Dominic De Nardo  4 ,  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.
PMID: 37723181 DOI: 10.1038/s41467-023-41381-9
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.

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