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

Author

Listed:
  • Tomalika R. Ullah

    (Hudson Institute of Medical Research
    Monash University)

  • 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
    Monash University)

  • Linden J. Gearing

    (Hudson Institute of Medical Research
    Monash University)

  • James Roest

    (St. Vincent’s Institute of Medical Research)

  • Julian P. Vivian

    (St. Vincent’s Institute of Medical Research
    The University of Melbourne)

  • Sunil Sapkota

    (Hudson Institute of Medical Research
    Monash University)

  • W. Samantha N. Jayasekara

    (Hudson Institute of Medical Research
    Monash University)

  • Daniel S. Wenholz

    (Noxopharm Limited
    UNSW Sydney)

  • 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
    Monash University
    Monash Medical Centre)

  • Arwaf S. Alharbi

    (Hudson Institute of Medical Research
    Monash University
    Taif University)

  • Refaya Rezwan

    (Hudson Institute of Medical Research
    Monash University)

  • Meredith O’Keeffe

    (Monash Biomedicine Discovery Institute, Monash University)

  • William A. Donald

    (UNSW Sydney)

  • Julia I. Ellyard

    (Australian National University
    Australian National University)

  • Wilson Wong

    (Hudson Institute of Medical Research
    Monash University
    Hudson Institute of Medical Research)

  • Naresh Kumar

    (UNSW Sydney)

  • Benjamin T. Kile

    (Monash Biomedicine Discovery Institute, Monash University
    University of Adelaide)

  • Carola G. Vinuesa

    (Australian National University
    Australian National University
    Francis Crick Institute)

  • 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
    Monash University)

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.

Suggested Citation

  • 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 & Vi, 2023. "Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41381-9
    DOI: 10.1038/s41467-023-41381-9
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    References listed on IDEAS

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