The current standard of treatment against tuberculosis consists of a cocktail of first-line drugs, including isoniazid and pyrazinamide. Although these drugs are known to be bactericidal, contribution of host cell responses in the context of antimycobacterial chemotherapy, if any, remains unknown. We demonstrate that isoniazid and pyrazinamide promote autophagy activation and phagosomal maturation in Mycobacterium tuberculosis (Mtb)-infected host cells. Treatment of Mtb-infected macrophages with isoniazid or pyrazinamide caused significant activation of cellular and mitochondrial reactive oxygen species and autophagy, which was triggered by bacterial hydroxyl radical generation. Mycobacterium marinum-infected autophagy-defective, atg7 mutant Drosophila exhibited decreased survival rates, which could not be rescued by antimycobacterial treatment, indicating that autophagy is required for effective antimycobacterial drug action in vivo. Moreover, activation of autophagy by antibiotic treatment dampened Mtb-induced proinflammatory responses in macrophages. Together, these findings underscore the importance of host autophagy in orchestrating successful antimicrobial responses to mycobacteria during chemotherapy.
Bibliographical noteFunding Information:
We thank Dr. R.L. Modlin (University of California, Los Angeles) and Dr. M.H. Roh (University of Michigan Health System) for helpful comments and critical reading of the manuscript; Dr. Y.S. Bae (Ewha University, Seoul, Korea) for kind provision of NOX2 KO mice; Dr. R.L. Friedman (University of Arizona) for kind provision of mycobacterial strains; Dr. T.P. Neufeld (University of Minnesota) for kind provision of drosophila strains; and K.-H. Kim (Chungnam National University) and D.-H. Choi (Korea Research Institute of Bioscience and Biotechnology) for excellent technical assistance. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2012-0005763) through the Infection Signaling Network Research Center at Chungnam National University.
All Science Journal Classification (ASJC) codes