Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. The host-directed therapy is a promising strategy for TB treatment that synergize with anti-TB treatment drugs. In this study, we found that the anti-chronic lymphocytic leukemia drug, ibrutinib, inhibited the growth of intracellular Mtb in human macrophages. Mechanisms studies showed that ibrutinib treatment significantly decreased p62 and increased LC3b proteins in Mtb infected macrophages. In addition, ibrutinib increased LC3b colocalization with intracellular Mtb and auto-lysosome fusion. Furthermore, inhibition of autophagy by using siRNA targeting ATG7 abolished the effect of ibrutinib-mediated suppression of intracellular Mtb. Next, we found that ibrutinib induced autophagy was through inhibition of BTK/Akt/mTOR pathway. Finally, we confirmed that ibrutinib treatment significantly reduced Mtb load in mediastinal node and spleen of Mtb infected mice. In conclusion, our data suggest that ibrutinib is a potential host-directed therapy candidate against TB.

中文翻译：

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依鲁替尼通过诱导巨噬细胞自噬抑制细胞内结核分枝杆菌的生长。

结核病（TB）是全世界发病率和死亡率的主要原因。宿主定向疗法是与抗结核治疗药物协同作用的结核病治疗的有前途的策略。在这项研究中，我们发现抗慢性淋巴细胞性白血病药物依鲁替尼可抑制人巨噬细胞内Mtb的生长。机制研究表明，依鲁替尼治疗可显着降低Mtb感染巨噬细胞中的p62和LC3b蛋白。此外，依鲁替尼可增加LC3b与细胞内Mtb和自溶酶体融合的共定位作用。此外，通过使用靶向ATG7的siRNA抑制自噬消除了依鲁替尼介导的细胞内Mtb抑制作用。接下来，我们发现依鲁替尼诱导的自噬是通过抑制BTK / Akt / mTOR途径实现的。最后，我们证实依鲁替尼治疗可显着降低Mtb感染小鼠纵隔淋巴结和脾脏中的Mtb负荷。总之，我们的数据表明，依鲁替尼是潜在的针对结核病的宿主定向治疗候选药物。