Oral Presentation Lorne Infection and Immunity 2023

Pharmacological inhibition of TBK1/IKKε blunts COVID-19 immunopathology (#42)

Tomalika Ullah 1 2 , Matt Johansen 3 , Daniel Wenholz 4 , Olivier Laczka 4 , Philip Hansbro 3 , Dominic De Nardo 5 , Michael Gantier 1 2
  1. Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Molecular and Translational Science, Monash University , Clayton, Victoria , Australia
  3. Centenary Institute, University of Technology Sydney, Sydney, NSW, Australia
  4. Noxopharm, Chatswood, NSW, Australia
  5. Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

TANK-binding kinase 1 (TBK1) is a key signalling component that drives the production of type-I interferons (IFNs), which have essential antiviral activities including against SARSCoV-2. TBK1 and its homolog IκB kinase-ε (IKKε) can also induce the production of proinflammatory factors that contribute to pathogen clearance. While initially protective, delayed engagement of type-I IFN is associated with lethal hyper-inflammation seen in severe COVID-19 patients. The contribution of TBK1/IKKε signalling to this response is unknown. We have discovered that the anticancer small molecule idronoxil inhibits both IRF3 and NF-κB-driven inflammation by disrupting the formation of TBK1/IKKε signalling complexes following STING activation. Leveraging this unique activity, we show that therapeutic administration of idronoxil suppresses cellular and molecular lung inflammation in K18-hACE2 mice challenged with SARS-CoV-2, resulting in reduced pro-inflammatory cytokine production and decreased airway fibrosis in experimental COVID-19. Our results indicate a critical role for TBK1/IKKε signalling in SARS-CoV-2 hyper-inflammation and identify a novel therapeutic intervention to limit disease severity in COVID-19 patients.