Pharmacological inhibition of TBK1/IKKε blunts COVID-19 immunopathology

Abstract 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 SARS-CoV-2. TBK1 and its homolog IκB kinase-ε (IKKε) can also induce the production of pro-inflammatory 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 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.