Mycobacterium tuberculosis (MTB) infection could induce death of host human macrophages, promoting bacterial spread. In the current study we tested the potential role of microRNA-579 (miR-579) in the death of macrophages infected with MTB. In the primary human macrophages MTB infection induced upregulation of miR-579 but downregulation of its mRNA targets, S1RT1 and PDK1, which were accompanied by significant macrophage death and apoptosis. miR-579 inhibition, by its anti-sense sequence, restored SIRT1-PDK1 expression and significantly attenuated MTB-induced cytotoxicity and apoptosis in human macrophages. Conversely, ectopic overexpression of miR-579 further downregulated SIRT1-PDK1 expression and exacerbated MTB-induced cytotoxicity in human macrophages. Further studies showed that cPWWP2A, the miR-579's endogenous sponge circRNA, was downregulated in MTB-infected macrophages. Conversely, forced overexpression of cPWWP2A, by a recombinant adeno-associated virus construct, reversed MTB-induced miR-579 upregulation and macrophage cytotoxicity. Taken together, our results show that miR-579 upregulation mediates MTB-induced macrophage cytotoxicity. Targeting cPWWP2A-miR-579 axis could be a novel strategy to protect human macrophages from MTB infection. (C) 2019 Elsevier Inc. All rights reserved.