HDAC6介导的自噬在结核抵抗者产生中的作用机制

结核抵抗者（Resister）是指能将反复大量入侵的结核分枝杆菌（Mtb）完全清除的特殊人群。探究Resister产生机制对于实现易感人群精准干预，开辟结核免疫治疗的新途径具有重要意义，但其机制尚不清楚。我们前期研究发现Resister巨噬细胞对Mtb具有更强的杀灭作用，且组蛋白去乙酰化酶6（HDAC6）特异高表达于Resister巨噬细胞，对巨噬细胞清除Mtb可能有重要作用。据此提出假说Resister的巨噬细胞通过特异上调HDAC6介导的自噬，促进巨噬细胞对Mtb的杀灭作用。本研究拟利用原代巨噬细胞明确HDAC6对于噬细胞杀灭Mtb的作用；通过自噬流和蛋白可视化定量技术等探讨HDAC6表达对自噬分子信号通路的调控机制；利用细胞和动物模型评价HDAC6表达对自噬及巨噬细胞清除Mtb的影响，以阐明Resister产生的天然免疫机制，为探索预防结核感染及提高结核疗效的免疫干预策略奠定基础。

TB resistant (Resister) refers to a special population that can completely eliminate the Mycobacterium tuberculosis (Mtb) after long-term and large amount exposure to Mtb. Exploring the mechanism of resister is of great significance for achieving precise intervention in early high-risk populations and opening up a new approach to tuberculosis immunotherapy, but it remains unclear. Our previous study found that resister macrophages had a stronger killing effect on Mtb, and protein deacetylase 6 (HDAC6) was specifically highly expressed in resister macrophages, which may play an important role in the clearance of Mtb by macrophages. It was hypothesized that the macrophages of Resister specifically up-regulated HCDA6-mediated autophagy to promote the capability of macrophages to kill Mtb. In this study, primary macrophages were used as the model to determine the role of HDAC6 in killing Mtb by macrophages. The regulation mechanism of HDAC6 expression level on autophagy molecular signaling pathway was investigated by autophagy flow and protein visualization and quantitative techniques. Cell model and animal model were used to evaluate the effect of HDAC6 expression on the clearance of Mtb infection by macrophages, so as to elucidate the natural immune mechanism generated by resister, and lay a theoretical foundation for the formulation of effective intervention strategies to block the infection of TB susceptible populations and the improvement of immunotherapy programs for active TB patients.