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

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

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. Michael.gantier@hudson.org.au.
  • 18 Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. Michael.gantier@hudson.org.au.
  • # 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.

Figures
Products