title: Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action.
abstract: 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.
authors.affiliation: Department of Microbiology, Chungnam National University, Daejeon, Korea.
authors.forename: Jwa-Jin
authors.initials: JJ
authors.lastname: Kim
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Lee
authors.forename: Dong-Min
authors.initials: DM
authors.lastname: Shin
authors.forename: Wonho
authors.initials: W
authors.lastname: Kim
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Yuk
authors.forename: Hyo Sun
authors.initials: HS
authors.lastname: Jin
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Guang-Ho
authors.initials: GH
authors.lastname: Cha
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Zee-Won
authors.initials: ZW
authors.lastname: Lee
authors.forename: Sung Jae
authors.initials: SJ
authors.lastname: Shin
authors.forename: Heekyung
authors.initials: H
authors.lastname: Yoo
authors.forename: Young Kil
authors.initials: YK
authors.lastname: Park
authors.forename: Jin Bong
authors.initials: JB
authors.lastname: Park
authors.forename: Jongkyeong
authors.initials: J
authors.lastname: Chung
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D001343:Autophagy / Q000276:immunology*; D000071193:Autophagy-Related Protein 7; D002478:Cells, Cultured; D004330:Drosophila; D029721:Drosophila Proteins / Q000172:deficiency / Q000276:immunology; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D019910:Mycobacterium marinum / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology* / Q000472:pathogenicity; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D011718:Pyrazinamide / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D000995:Antitubercular Agents; C530193:Atg7 protein, Drosophila; D029721:Drosophila Proteins; D017382:Reactive Oxygen Species; D011718:Pyrazinamide; D000071193:Autophagy-Related Protein 7; D007538:Isoniazid