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.
| Original language | English |
|---|---|
| Pages (from-to) | 457-468 |
| Number of pages | 12 |
| Journal | Cell Host and Microbe |
| Volume | 11 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2012 May 17 |
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All Science Journal Classification (ASJC) codes
- Parasitology
- Microbiology
- Virology
Cite this
}
Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. © 2012 Elsevier Inc. / Kim, Jwa Jin; Lee, Hye Mi; Shin, Dong Min; Kim, Wonho; Yuk, Jae Min; Jin, Hyo Sun; Lee, Sang Hee; Cha, Guang Ho; Kim, Jin Man; Lee, Zee Won; Shin, Sung Jae; Yoo, Heekyung; Park, Young Kil; Park, Jin Bong; Chung, Jongkyeong; Yoshimori, Tamotsu; Jo, Eun Kyeong.
In: Cell Host and Microbe, Vol. 11, No. 5, 17.05.2012, p. 457-468.Research output: Contribution to journal › Article
TY - JOUR
T1 - Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. © 2012 Elsevier Inc.
AU - Kim, Jwa Jin
AU - Lee, Hye Mi
AU - Shin, Dong Min
AU - Kim, Wonho
AU - Yuk, Jae Min
AU - Jin, Hyo Sun
AU - Lee, Sang Hee
AU - Cha, Guang Ho
AU - Kim, Jin Man
AU - Lee, Zee Won
AU - Shin, Sung Jae
AU - Yoo, Heekyung
AU - Park, Young Kil
AU - Park, Jin Bong
AU - Chung, Jongkyeong
AU - Yoshimori, Tamotsu
AU - Jo, Eun Kyeong
PY - 2012/5/17
Y1 - 2012/5/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84861180818&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84861180818&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2012.03.008
DO - 10.1016/j.chom.2012.03.008
M3 - Article
C2 - 22607799
AN - SCOPUS:84861180818
VL - 11
SP - 457
EP - 468
JO - Cell Host and Microbe
JF - Cell Host and Microbe
SN - 1931-3128
IS - 5
ER -