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

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posted on 2023-09-22, 13:37 authored by 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, 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 G Vinuesa, Graham E Kelly, Olivier F Laczka, Philip M Hansbro, Dominic De Nardo, Michael P Gantier
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.

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Crick (Grant ID: CC2228, Grant title: Vinuesa CC2228)

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