Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection.
Tomalika R UllahMatt D JohansenKatherine R BalkaRebecca L AmbroseLinden J GearingJames RoestJulian P VivianSunil SapkotaW Samantha N JayasekaraDaniel S WenholzVina R AldillaJun ZengStefan MiemczykDuc H NguyenNicole G HansbroRajan VenkatramanJung Hee KangEe Shan PangBelinda J ThomasArwaf S AlharbiRefaya RezwanMeredith O'KeeffeW Alexander DonaldJulia I EllyardWilson WongNaresh KumarBenjamin T KileCarola G VinuesaGraham E KellyOlivier F LaczkaPhilip Michael HansbroDominic De NardoMichael P GantierPublished in: Nature communications (2023)
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.