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

Ullah, TR; Johansen, MD; Balka, KR; Ambrose, RL; Gearing, LJ; Roest, J; Vivian, JP; Sapkota, S; Jayasekara, WSN; Wenholz, DS; Aldilla, VR; Zeng, J; Miemczyk, S; Nguyen, DH; Hansbro, NG; Venkatraman, R; Kang, JH; Pang, ES; Thomas, BJ; Alharbi, AS; Rezwan, R; O'Keeffe, M; Donald, WA; Ellyard, JI; Wong, W; Kumar, N; Kile, BT; Vinuesa, CG; Kelly, GE; Laczka, OF; Hansbro, PM; De Nardo, D; Gantier, MP

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

Ullah, TR Johansen, MD Balka, KR Ambrose, RL Gearing, LJ Roest, J Vivian, JP Sapkota, S Jayasekara, WSN Wenholz, DS Aldilla, VR Zeng, J Miemczyk, S Nguyen, DH Hansbro, NG Venkatraman, R Kang, JH Pang, ES Thomas, BJ Alharbi, AS Rezwan, R O'Keeffe, M Donald, WA Ellyard, JI Wong, W Kumar, N Kile, BT Vinuesa, CG Kelly, GE Laczka, OF Hansbro, PM De Nardo, D Gantier, MP

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Publisher:: NATURE PORTFOLIO
Publication Type:: Journal Article
Citation:: Nat Commun, 2023, 14, (1), pp. 5666
Issue Date:: 2023-09-18

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Field	Value	Language
dc.contributor.author	Ullah, TR
dc.contributor.author	Johansen, MD
dc.contributor.author	Balka, KR
dc.contributor.author	Ambrose, RL
dc.contributor.author	Gearing, LJ
dc.contributor.author	Roest, J
dc.contributor.author	Vivian, JP
dc.contributor.author	Sapkota, S
dc.contributor.author	Jayasekara, WSN
dc.contributor.author	Wenholz, DS
dc.contributor.author	Aldilla, VR
dc.contributor.author	Zeng, J
dc.contributor.author	Miemczyk, S
dc.contributor.author	Nguyen, DH
dc.contributor.author	Hansbro, NG
dc.contributor.author	Venkatraman, R
dc.contributor.author	Kang, JH
dc.contributor.author	Pang, ES
dc.contributor.author	Thomas, BJ
dc.contributor.author	Alharbi, AS
dc.contributor.author	Rezwan, R
dc.contributor.author	O'Keeffe, M
dc.contributor.author	Donald, WA
dc.contributor.author	Ellyard, JI
dc.contributor.author	Wong, W
dc.contributor.author	Kumar, N
dc.contributor.author	Kile, BT
dc.contributor.author	Vinuesa, CG
dc.contributor.author	Kelly, GE
dc.contributor.author	Laczka, OF
dc.contributor.author	Hansbro, PM
dc.contributor.author	De Nardo, D
dc.contributor.author	Gantier, MP
dc.date.accessioned	2024-01-25T05:46:17Z
dc.date.available	2023-09-03
dc.date.available	2024-01-25T05:46:17Z
dc.date.issued	2023-09-18
dc.identifier.citation	Nat Commun, 2023, 14, (1), pp. 5666
dc.identifier.issn	2041-1723
dc.identifier.issn	2041-1723
dc.identifier.uri	http://hdl.handle.net/10453/174954
dc.description.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.
dc.format	Electronic
dc.language	eng
dc.publisher	NATURE PORTFOLIO
dc.relation	http://purl.org/au-research/grants/nhmrc/1175134
dc.relation.ispartof	Nat Commun
dc.relation.isbasedon	10.1038/s41467-023-41381-9
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	I-kappa B Kinase
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	COVID-19
dc.subject.mesh	SARS-CoV-2
dc.subject.mesh	Inflammation
dc.subject.mesh	Interferon Type I
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	Inflammation
dc.subject.mesh	Interferon Type I
dc.subject.mesh	I-kappa B Kinase
dc.subject.mesh	COVID-19
dc.subject.mesh	SARS-CoV-2
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	I-kappa B Kinase
dc.subject.mesh	Disease Models, Animal
dc.subject.mesh	COVID-19
dc.subject.mesh	SARS-CoV-2
dc.subject.mesh	Inflammation
dc.subject.mesh	Interferon Type I
dc.title	Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection.
dc.type	Journal Article
utslib.citation.volume	14
utslib.location.activity	England
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	open_access	*
dc.date.updated	2024-01-25T05:46:12Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	14
utslib.citation.issue	1

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/174954