Mo Siwei, Liu Xiaoqian, Zhang Kehong, Wang Wenfei, Cai Yi, Ouyang Qi, Zhu Chuanzhi, Lin Dachuan, Wan Haoqiang, Li Dechang, Wen Zhihua, Chen Xinchun
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, School of Medicine, Shenzhen University, Shenzhen, China.
Department of Infectious Disease, Shenzhen People's Hospital, Second Clinical Medical College of Jinan University, Shenzhen, Guangdong Province, China.
J Leukoc Biol. 2022 May;111(5):1021-1029. doi: 10.1002/JLB.4A0221-119RR. Epub 2021 Sep 17.
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.
结核病（TB）是由结核分枝杆菌（Mtb）引起的一种传染性细菌性疾病，是全球主要的死亡原因之一。耐多药结核病仍然是一场公共卫生危机，因此迫切需要新型有效的治疗方法，如宿主导向疗法（HDTs），以应对结核病感染带来的挑战。在本研究中，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）水平升高所诱导的。我们进一步发现，在感染Mtb的巨噬细胞中，CaM的表达降低，而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，在CaM沉默或CAMKII活性受到抑制后，巨噬细胞的抗结核能力降低。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，我们的研究结果有力地支持了对这种目前已获批准的药物作为结核病治疗HDT候选药物进行进一步研究。
