Viperin inhibits interferon-γ production to promote Mycobacteria tuberculosis infection by disrupting TBK1-IKKε-IRF3-axis and JAK-STAT signaling

Abstract

Abstract As an interferon-inducible protein, Viperin has demonstrated the advantages of a broad-spectrum antiviral effects and regulation of host immune responses. However, how Viperin regulates interferon-γ (IFN-γ) production in macrophages to control Mycobacterium tuberculosis (Mtb) infection remain undefined. Here, we demonstrated that Viperin inhibited IFN-γ production in macrophages and in lungs of mice to promote Mtb infection. Further insight into the mechanism 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 TBK1-IKKε-IRF3 axis restored the IFN-γ production reduced by Viperin knockout in bone marrow derived macrophage (BMDM) and suppressed Mtb infection. 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. In addition, a combination of the anti-TB drug INH treatment in the absence of Viperin resulted in further activation of TBK1-IKKε-IRF3 axis and JAK1, and led to further IFN-γ production and anti-TB effect in BMDM. This study highlights the involvement of TBK1-IKKε-IRF3 axis and JAK-STAT signaling pathway 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. Thus, we propose Viperin as a candidate target for host-directed therapy (HDT) for TB treatment.