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

Journal article


Ullah, Tomalika R., Johansen, Matt D., Balka, Katherine R., Ambrose, Rebecca L., Gearing, Linden J., Roest, James, Vivian, Julian Philip, Sapkota, Sunil, Jayasekara, W. Samantha N., Wenholz, Daniel S., Aldilla, Vina R., Zeng, Jun, Miemczyk, Stefan, Nguyen, Duc H. and et. al.. (2023). Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection. Nature Communications. 14(1), pp. 1-13. https://doi.org/10.1038/s41467-023-41381-9
AuthorsUllah, Tomalika R., Johansen, Matt D., Balka, Katherine R., Ambrose, Rebecca L., Gearing, Linden J., Roest, James, Vivian, Julian Philip, Sapkota, Sunil, Jayasekara, W. Samantha N., Wenholz, Daniel S., Aldilla, Vina R., Zeng, Jun, Miemczyk, Stefan, Nguyen, Duc H. and et. al.
Abstract

TANK-binding kinase 1 (TBK1) is a key signalling component in the pro-duction 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.

KeywordsInnate immunity; Target identification; Viral infection
Year01 Jan 2023
JournalNature Communications
Journal citation14 (1), pp. 1-13
PublisherNature Publishing Group
ISSN2041-1723
Digital Object Identifier (DOI)https://doi.org/10.1038/s41467-023-41381-9
Web address (URL)https://www.nature.com/articles/s41467-023-41381-9
Open accessPublished as ‘gold’ (paid) open access
Research or scholarlyResearch
Page range1-13
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication process dates
Completed18 Sep 2023
Deposited09 Apr 2024
Additional information

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Place of publicationUnited Kingdom
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