Interferon regulatory factor 1 eliminates mycobacteria by suppressing p70 S6 kinase via mechanistic target of rapamycin signaling. Issue 3 (September 2019)

• Record Type: Journal Article
• Authors: Zhou, Xinying; Yang, Jiahui; Zhang, Zelin; Zhang, Lijie; Lie, Linmiao; Zhu, Bo; Xu, Lei; Gao, Yuchi; Du, Xialin; Huang, Yingqi; Wang, Ruining; Liu, Honglin; Li, Yanfen; Hu, Shengfeng; Zhou, Chaoying; Wen, Qian; Pan, Qiuwei; Ma, Li
• Is Part Of: Journal of infection. Volume 79:Issue 3(2019)
• Page Start: 262
• Page End: 276
• Publication Date: 2019-09
• Subjects: Mycobacterium tuberculosis (Mtb) -- Interferon regulatory factor 1 (IRF1) -- Macrophages (Mϕs) -- Mechanistic target of rapamycin signaling (mTOR) -- p70 S6 kinase (p70 S6K); IRF1 interferon regulatory factor 1 -- ISGs interferon-stimulated genes -- Mtb Mycobacterium tuberculosis -- iNOS inducible nitric oxide synthase -- TB tuberculosis -- Mϕs macrophages -- hMDMs human monocyte-derived macrophages -- THP-1-Mϕ THP-1-derived macrophages -- mTOR mechanistic target of rapamycin -- p70 S6K p70 S6 kinase -- INH isoniazid -- IFNs interferons -- STAT signal transducer and activator of transcription -- EMT epithelial-mesenchymal-transition -- DMSO dimethylsulfoxide -- FBS fetal bovine serum -- GM-CSF granulocyte macrophage colony-stimulating factor -- PMA phorbol-12-myristate-13-acetate -- Fluc Photinus pyralis luciferase -- RFP red fluorescent protein -- OADC oleic acid-albumin-dextrose-catalase -- CFU colony-forming units -- Atgs autophagy-related genes -- RNS reactive nitrogen species -- ROS reactive oxidative species -- DTT DL-Dithiothreitol -- PRRs pattern recognition receptors -- TLR toll-like receptor -- LPS lipopolysaccharide -- DUOX2 dual oxidases 2 -- NOX NADPH oxidase -- MMPs matrix metalloproteinases -- ChIP-seq chromatin immunoprecipitation-sequencing -- MAPKs mitogen-activated protein kinases -- LAMP1 lysosome-associated membrane protein 1 -- 3-MA 3-methyladenine -- NO nitric oxide -- dsRNA double-stranded RNA; Infection -- Periodicals; Bacterial Infections -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.905
• DOI: 10.1016/j.jinf.2019.06.007
• Languages: English
• ISSNs: 0163-4453

Abstract

Highlights: IRF1 is induced in pulmonary TB patients in vivo and in human Mϕs in vitro . IRF1 protects human Mϕs from Mtb infection. IRF1 promotes the expression of several pro-inflammatory cytokines. IRF1 suppresses the mTOR/ p70 S6K cascade to exert its anti-Mtb effect. Summary: Objectives: Although it has been reported that Interferon regulatory factor 1 (IRF1) inhibits Mycobacterium tuberculosis (Mtb) infection via inducible nitric oxide synthase (iNOS) in mice, how it counteracts with mycobacterial infection in human remains largely obscure. This study was conducted to investigated the effect of IRF1 on Mtb infection in human macrophages (Mϕs). Methods: We thus investigated the IRF1 expression by using PBMC and monocytes of pulmonary tuberculosis (TB) patients and human monocyte-derived macrophages (hMDMs) and THP-1-derived macrophages (THP-1-Mϕ). We used gain-of-function and loss-of-function approaches to explore the role of IRF1 on Mtb infection. Results: IRF1 was significantly induced in PBMC and monocytes of pulmonary TB patients in vivo and in human Mϕs in vitro . We demonstrated that IRF1 protects Mϕs from Mtb infection. Concurrently, IRF1 promotes the expression of several pro-inflammatory cytokines including IL-6, TNF-α and IL-8, indicating IRF1-mediated activation of innate immunity upon Mtb infection. Gain-of-function and loss-of-function approaches have demonstrated that IRF1 suppresses the mechanistic target of rapamycin (mTOR)/p70 S6 kinase (p70 S6K) cascade to exert its anti-Mtb effect. Conclusions: The discovery of a novel function of IRF1 in facilitating anti-mycobacterial effect through suppressing mTOR/p70 S6K signaling in Mϕs may provide a promoting therapeutic target for tuberculosis.