Viperin inhibits interferon-γ production to promote Mycobacterium tuberculosis survival by disrupting TBK1-IKKε-IRF3-axis and JAK-STAT signaling.
Inflamm Res
; 73(6): 897-913, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38625657
ABSTRACT
OBJECTIVES AND DESIGN:
As an interferon-inducible protein, Viperin has broad-spectrum antiviral effects and regulation of host immune responses. We aim to investigate how Viperin regulates interferon-γ (IFN-γ) production in macrophages to control Mycobacterium tuberculosis (Mtb) infection.METHODS:
We use Viperin deficient bone-marrow-derived macrophage (BMDM) to investigate the effects and machines of Viperin on Mtb infection.RESULTS:
Viperin inhibited IFN-γ production in macrophages and in the lung of mice to promote Mtb survival. Further insight into the mechanisms of Viperin-mediated regulation of IFN-γ production revealed the role of TANK-binding kinase 1 (TBK1), the TAK1-dependent inhibition of NF-kappa B kinase-epsilon (IKKε), and interferon regulatory factor 3 (IRF3). Inhibition of the TBK1-IKKε-IRF3 axis restored IFN-γ production reduced by Viperin knockout in BMDM and suppressed intracellular Mtb survival. Moreover, Viperin deficiency activated the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway, which promoted IFN-γ production and inhibited Mtb infection in BMDM. Additionally, a combination of the anti-TB drug INH treatment in the absence of Viperin resulted in further IFN-γ production and anti-TB effect.CONCLUSIONS:
This study highlights the involvement of TBK1-IKKε-IRF3 axis and JAK-STAT signaling pathways in Viperin-suppressed IFN-γ production in Mtb infected macrophages, and identifies a novel mechanism of Viperin on negatively regulating host immune response to Mtb infection.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
2_ODS3
/
3_ND
Problema de saúde:
2_enfermedades_transmissibles
/
3_neglected_diseases
/
3_tuberculosis
Assunto principal:
Transdução de Sinais
/
Proteínas
/
Interferon gama
/
Proteínas Serina-Treonina Quinases
/
Fator Regulador 3 de Interferon
/
Macrófagos
/
Camundongos Endogâmicos C57BL
/
Mycobacterium tuberculosis
Limite:
Animals
Idioma:
En
Revista:
Inflamm Res
Assunto da revista:
ALERGIA E IMUNOLOGIA
/
PATOLOGIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China