Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infectionMore about Open Access at the Crick
Authors listTomalika 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 Vina R Aldilla Jun Zeng Stefan Miemczyk Duc H Nguyen Nicole G Hansbro Rajan Venkatraman Jung Hee Kang Ee Shan Pang Belinda J Thomas Arwaf S Alharbi Refaya Rezwan Meredith O'Keeffe William A Donald Julia I Ellyard Wilson Wong Naresh Kumar Benjamin T Kile Carola Vinuesa Graham E Kelly Olivier F Laczka Philip M Hansbro Dominic De Nardo Michael P Gantier
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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.
Journal Nature Communications
Issue number 1