| First Author | Ullah TR | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 5666 |
| PubMed ID | 37723181 | Mgi Jnum | J:340733 |
| Mgi Id | MGI:7530290 | Doi | 10.1038/s41467-023-41381-9 |
| Citation | Ullah TR, et al. (2023) Pharmacological inhibition of TBK1/IKKepsilon blunts immunopathology in a murine model of SARS-CoV-2 infection. Nat Commun 14(1):5666 |
| abstractText | 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 IkappaB kinase-epsilon (IKKepsilon), 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/IKKepsilon signalling to these responses is unknown. Here we find that the small molecule idronoxil inhibits TBK1/IKKepsilon signalling through destabilisation of TBK1/IKKepsilon protein complexes. Treatment with idronoxil, or the small molecule inhibitor MRT67307, suppresses TBK1/IKKepsilon 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/IKKepsilon signalling in SARS-CoV-2 hyper-inflammation. |
