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- Title
Viperin inhibits interferon-γ production to promote Mycobacterium tuberculosis survival by disrupting TBK1-IKKε-IRF3-axis and JAK-STAT signaling.
- Authors
Liang, Yao; Liang, Yun; Wang, Qi; Li, Qianna; Huang, Yingqi; Li, Rong; Pan, Xiaoxin; Lie, Linmiao; Xu, Hui; Han, Zhenyu; Liu, Honglin; Wen, Qian; Zhou, Chaoying; Ma, Li; Zhou, Xinying
- 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.
- Subjects
MYCOBACTERIUM tuberculosis; JAK-STAT pathway; INTERFERON regulatory factors; IMMUNOREGULATION; ISONIAZID
- Publication
Inflammation Research, 2024, Vol 73, Issue 6, p897
- ISSN
1023-3830
- Publication type
Article
- DOI
10.1007/s00011-024-01873-w