Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection
Tomalika R. Ullah, Matt D. Johansen, Katherine R. Balka, Rebecca L Ambrose, Linden J. Gearing, James Roest, J.P. Vivian, Sunil Sapkota, W. Samantha N. Jayasekara, Daniel S. Wenholz, Vina R. Aldilla, Jun Zeng, Stefan Miemczyk, Duc Hai Nguyen, Nicole G. Hansbro, Rajan Venkatraman, Jung Hee Kang, Ee Shan Pang, Belinda J. Thomas, Arwaf Alharbi, Refaya Rezwan, Meredith O’Keeffe, William A. Donald, Julia I. Ellyard, Wilson Wong, Naresh Kumar, Benjamin T. Kile, Carola G. Vinuesa, Graham Kelly, Olivier Laczka, Philip M. Hansbro, Dominic De Nardo, Michael P. Gantier
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.