Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.
Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou, China.
Inflamm Res. 2024 Jun;73(6):897-913. doi: 10.1007/s00011-024-01873-w. Epub 2024 Apr 16.
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.
We use Viperin deficient bone-marrow-derived macrophage (BMDM) to investigate the effects and machines of Viperin on Mtb infection.
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.
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.
Viperin 作为一种干扰素诱导蛋白，具有广谱抗病毒作用和调节宿主免疫反应的功能。我们旨在研究 Viperin 如何调节巨噬细胞中的干扰素-γ（IFN-γ）产生，以控制结核分枝杆菌（Mtb）感染。
我们使用 Viperin 缺陷型骨髓来源的巨噬细胞（BMDM）来研究 Viperin 对 Mtb 感染的影响和机制。
Viperin 抑制了巨噬细胞和小鼠肺部的 IFN-γ产生，从而促进了 Mtb 的存活。进一步深入研究 Viperin 介导的 IFN-γ产生调节机制表明，TANK 结合激酶 1（TBK1）、TAK1 依赖性 NF-κB 激酶-ε（IKKε）抑制和干扰素调节因子 3（IRF3）发挥了作用。抑制 TBK1-IKKε-IRF3 轴可恢复 BMDM 中由 Viperin 敲除引起的 IFN-γ产生减少，并抑制细胞内 Mtb 的存活。此外，Viperin 缺陷激活了 Janus 激酶（JAK）-信号转导和转录激活因子（STAT）信号通路，促进了 IFN-γ产生，并抑制了 BMDM 中的 Mtb 感染。此外，在没有 Viperin 的情况下，联合使用抗结核药物 INH 治疗可进一步增加 IFN-γ 产生并增强抗结核作用。
本研究强调了 TBK1-IKKε-IRF3 轴和 JAK-STAT 信号通路在 Viperin 抑制 Mtb 感染的巨噬细胞中 IFN-γ产生中的作用，并确定了 Viperin 负调控宿主对 Mtb 感染免疫反应的新机制。
