干扰素调节因子1调控巨噬细胞自噬在抗结核免疫中的效应与机制

As a potent medication for drug-resistance tuberculosis (TB), treatment of interferon (IFNs) on TB has been used in clinic with high efficiency and diversity. Interferon regulatory factor 1 (IRF1) is one of the most important interferon stimulating gene (ISGs) downstream of the IFN signaling pathway and regulates the host immune response to combat pathogenic microorganism infection. However, the effects and mechanisms of IRF1 on the anti-TB immunity in human macrophages (Mφ) are unclear. Our previous results found that IRF1 expression was significantly increased in PBMCs and monocytes of TB patients and Mycobacterium tuberculosis （Mtb）infected Mφ. In addition, IRF1 promoted intracellular autophagy, regulated cell signaling pathways and inhibit Mtb survival in Mφ. Accordingly, we propose the hypothesis that "IRF1 regulates NF-κB, MAPK, JAK-STAT and mTOR signaling mediated autophagy to combat Mtb infection in Mφ." On this basis, we proposed to: i) confirm that Mtb infection induced IRF1 promotes autophagy to inhibit Mtb infection in Mφ; ii) determine the mechanism by which IRF1 regulates intracellular autophagy to clear Mtb. This project will reveal the effects and mechanisms of IRF1 on regulating intracellular autophagy to clear Mtb in Mφ, providing ideas for the development of new anti-TB immunotherapy targeting IRF1.

干扰素（IFNs）在临床上治疗结核（TB）具有高效性和多样性，是抵御耐药TB的高效药物。干扰素调节因子1（IRF1）是IFN信号通路下游最重要的干扰素刺激基因（ISGs）之一，能调控宿主免疫反应抵御病原微生物的感染，但IRF1调节人巨噬细胞（Mϕ）抗结核免疫的效应与机制尚不清楚。课题组前期研究发现，TB患者PBMC、单核细胞和结核分枝杆菌（Mtb）感染的Mϕ中IRF1表达显著增加；另外，IRF1促进细胞自噬，调控细胞信号通路，抑制胞内Mtb存活。据此，我们提出“IRF1调控Mϕ中NF-κB、MAPK、JAK-STAT和mTOR信号通路介导的自噬抗Mtb感染”的假说。在此基础上，拟：①证实Mtb感染Mϕ刺激增加的IRF1促进自噬抗Mtb感染；②探究IRF1调控胞内自噬清除Mtb的机制。项目将揭示IRF1调控Mϕ胞内自噬清除MTB的作用和机制，为开发以IRF1为靶标的抗结核免疫新疗法提供思路。

干扰素（IFNs）在临床上治疗结核（TB）具有高效性和多样性，是抵御耐药TB的高效药物。本课题筛选了28个巨噬细胞（Mφ）中结核分枝杆菌（Mtb）感染刺激表达变化的干扰素刺激基因（ISGs），确定干扰素调节因子1（IRF1）的表达随时间变化被诱导最显著。研究发现IRF1通过抑制mTOR-p70 S6K信号通路及促进自噬清除Mφ中Mtb感染，MxA通过抑制TAK1-IKKα/β-NF-κB信号通路促进Mφ中Mtb感染，另外，PKC-δ-mTOR信号通路通过抑制Mφ中GSK-3的活性，并通过MAPK ERK1/2上调MMP-1/9的表达，促进胞内Mtb感染。本项目通过研究宿主天然免疫反应对Mφ胞内Mtb的效应和机制，为IFNs治疗结核的多样性提供理论依据，为开发抗结核免疫新疗法提供思路。