Different Signaling Pathways Define Different Interferon-Stimulated Gene Expression during Mycobacteria Infection in Macrophages.
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) represents one of the greatest threats to human health., Interferons (IFNs) in combination with the first-line of anti-TB drugs have been used for treating TB for decades in the clinic, but how Mtb infection regulates interferon-stimulated genes (ISGs) in human macrophages (Mϕs) remains unknown. In this study, we investigated the expression-signature and associated innate signaling mechanisms of ISGs in Mtb-infected human monocyte-derived Mϕs (hMDMs) and THP-1-derived Mϕs (THP-1-Mϕs). Among 28 of the detected ISGs, 90% of them exerted a significant increase in Mtb-infected Mϕs. Additionally, we found that cytosolic cyclic (GMP-AMP) synthase (cGAS), toll-like receptor-2 (TLR-2) and TLR-4 signaling pathways participated in ISG induction. Their downstream elements of TANK-binding kinase 1 (TBK1), nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase-signal transducer and activator of transcription (JAK-STAT) were selectively involved in Mtb-mediated ISG production. Finally, the numerous types of ISG expression in hMDMs of TB patients were more susceptible to restimulation of Mtb infection or/and IFN treatment than that of healthy people. Hence, different signaling pathways define different ISG expression during Mtb infection and this helps to illustrate how ISGs are elucidated and to better understand the host immune responses to Mtb infection in Mϕs.
['Zhou|Xinying|X|', 'Yang|Jiahui|J|0000-0003-3777-8222', 'Zhang|Zelin|Z|', 'Zhang|Lijie|L|', 'Zhu|Bo|B|', 'Lie|Linmiao|L|', 'Huang|Yubin|Y|', 'Ma|Rui|R|', 'Zhou|Chaoying|C|', 'Hu|Shengfeng|S|', 'Wen|Qian|Q|', 'Ma|Li|L|0000-0001-5847-2375']
D000995:Antitubercular Agents D002478:Cells, Cultured D005786:Gene Expression Regulation D006801:Humans D007371:Interferon-gamma D053613:Janus Kinase 1 D020935:MAP Kinase Signaling System D008264:Macrophages D009169:Mycobacterium tuberculosis D016328:NF-kappa B D017346:Protein Serine-Threonine Kinases D050794:STAT1 Transcription Factor D015398:Signal Transduction D051195:Toll-Like Receptor 2 D051197:Toll-Like Receptor 4 D014397:Tuberculosis, Pulmonary
signaling pathways Mycobacterium tuberculosis (Mtb) interferon-stimulated genes (ISGs) macrophages (Mϕs)