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Flunarizine suppresses Mycobacterium tuberculosis growth via calmodulin-dependent phagosome maturation
Journal of Leukocyte Biology ( IF 5.5 ) Pub Date : 2021-09-17 , DOI: 10.1002/jlb.4a0221-119rr
Siwei Mo 1 , Xiaoqian Liu 2, 3 , Kehong Zhang 1, 4 , Wenfei Wang 1, 4 , Yi Cai 1 , Qi Ouyang 1 , Chuanzhi Zhu 5 , Dachuan Lin 1 , Haoqiang Wan 2 , Dechang Li 6 , Zhihua Wen 6 , Xinchun Chen 1
Affiliation  

Tuberculosis (TB), an infectious bacterial disease caused by Mycobacterium tuberculosis (Mtb), is a major cause of death worldwide. Multidrug-resistant TB remains a public health crisis and thus novel effective treatments, such as host-directed therapies (HDTs), are urgently required to overcome the challenges of TB infection. In this study, we evaluated 4 calcium modulators for their effects on Mtb growth in macrophages. Only flunarizine enhanced the bactericidal ability of macrophages against Mtb, which was induced by an increase in phosphorylated calcium/calmodulin (CaM)-dependent protein kinase II (pCaMKII) levels. We further discovered that the expression of CaM was decreased in Mtb-infected macrophages and restored following flunarizine treatment; this was associated with phagolysosome maturation and acidification. Consistent with these findings, the anti-TB ability of macrophages was reduced following the silencing of CaM or inhibition of CAMKII activity. In conclusion, our results demonstrated that flunarizine enhanced the bactericidal ability of macrophages and clarified its CaM–pCAMKII-dependent mechanism. Therefore, our findings strongly support further studies of this currently approved drug as an HDT candidate for TB therapy.

中文翻译:

氟桂利嗪通过钙调蛋白依赖性吞噬体成熟抑制结核分枝杆菌生长

结核病 (TB) 是一种由结核分枝杆菌( Mtb ) 引起的传染性细菌性疾病,是世界范围内死亡的主要原因。耐多药结核病仍然是一个公共卫生危机,因此迫切需要新的有效治疗方法,例如宿主导向疗法 (HDT),以克服结核病感染的挑战。在这项研究中,我们评估了 4 种钙调节剂对巨噬细胞中Mtb生长的影响。只有氟桂利嗪增强了巨噬细胞对Mtb的杀菌能力,这是由磷酸化钙/钙调蛋白 (CaM) 依赖性蛋白激酶 II (pCaMKII) 水平的增加引起的。我们进一步发现Mtb中 CaM 的表达降低- 感染巨噬细胞并在氟桂利嗪治疗后恢复;这与吞噬溶酶体的成熟和酸化有关。与这些发现一致,巨噬细胞的抗结核病能力在 CaM 沉默或 CAMKII 活性抑制后降低。总之,我们的结果表明氟桂利嗪增强了巨噬细胞的杀菌能力,并阐明了其 CaM-pCAMKII 依赖性机制。因此,我们的研究结果强烈支持进一步研究这种目前批准的药物作为结核病治疗的 HDT 候选药物。
更新日期:2021-09-17
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