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Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection.
Ullah, Tomalika R; Johansen, Matt D; Balka, Katherine R; Ambrose, Rebecca L; Gearing, Linden J; Roest, James; Vivian, Julian P; Sapkota, Sunil; Jayasekara, W Samantha N; Wenholz, Daniel S; Aldilla, Vina R; Zeng, Jun; Miemczyk, Stefan; Nguyen, Duc H; Hansbro, Nicole G; Venkatraman, Rajan; Kang, Jung Hee; Pang, Ee Shan; Thomas, Belinda J; Alharbi, Arwaf S; Rezwan, Refaya; O'Keeffe, Meredith; Donald, William A; Ellyard, Julia I; Wong, Wilson; Kumar, Naresh; Kile, Benjamin T; Vinuesa, Carola G; Kelly, Graham E; Laczka, Olivier F; Hansbro, Philip M; De Nardo, Dominic; Gantier, Michael P.
Afiliação
  • Ullah TR; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Johansen MD; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • Balka KR; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia.
  • Ambrose RL; Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
  • Gearing LJ; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Roest J; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • Vivian JP; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Sapkota S; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • Jayasekara WSN; St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
  • Wenholz DS; St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
  • Aldilla VR; Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia.
  • Zeng J; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Miemczyk S; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • Nguyen DH; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Hansbro NG; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • Venkatraman R; Noxopharm Limited, Chatswood, NSW, Australia.
  • Kang JH; School of Chemistry, UNSW Sydney, Kensington, NSW, Australia.
  • Pang ES; School of Chemistry, UNSW Sydney, Kensington, NSW, Australia.
  • Thomas BJ; MedChemSoft Solutions, Ferntree Gully, VIC, Australia.
  • Alharbi AS; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia.
  • Rezwan R; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia.
  • O'Keeffe M; Centre for Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia.
  • Donald WA; Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
  • Ellyard JI; Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
  • Wong W; Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
  • Kumar N; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Kile BT; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • Vinuesa CG; Monash Lung and Sleep, Monash Medical Centre, Clayton, VIC, Australia.
  • Kelly GE; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Laczka OF; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
  • Hansbro PM; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Turabah, Saudi Arabia.
  • De Nardo D; Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
  • Gantier MP; Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
Nat Commun ; 14(1): 5666, 2023 09 18.
Article em En | MEDLINE | ID: mdl-37723181
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Interferon Tipo I / COVID-19 Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Interferon Tipo I / COVID-19 Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article