Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, School of Medicine, Shenzhen University, Shenzhen 518055, China.
Yuebei Second People's Hospital, Shaoguan 512028, China.
J Infect. 2020 Jun;80(6):e19-e26. doi: 10.1016/j.jinf.2020.03.003. Epub 2020 Mar 11.
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.
结核病（TB）是全球发病率和死亡率的主要原因。宿主导向治疗是一种有前途的结核病治疗策略，可与抗结核治疗药物协同作用。在这项研究中，我们发现抗慢性淋巴细胞白血病药物伊布替尼抑制了人巨噬细胞内 Mtb 的生长。机制研究表明，伊布替尼治疗可显著降低 Mtb 感染巨噬细胞中的 p62 并增加 LC3b 蛋白。此外，伊布替尼增加了 LC3b 与细胞内 Mtb 的共定位和自噬体融合。此外，通过使用靶向 ATG7 的 siRNA 抑制自噬，消除了伊布替尼介导的抑制细胞内 Mtb 的作用。接下来，我们发现伊布替尼诱导的自噬是通过抑制 BTK/Akt/mTOR 通路。最后，我们证实伊布替尼治疗可显著降低 Mtb 感染小鼠纵隔淋巴结和脾脏中的 Mtb 负荷。总之，我们的数据表明伊布替尼是一种针对结核病的潜在宿主导向治疗候选药物。
