Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. © 2012 Elsevier Inc.

Jwa Jin Kim; Hye Mi Lee; Dong Min Shin; Wonho Kim; Jae Min Yuk; Hyo Sun Jin; Sang Hee Lee; Guang Ho Cha; Jin Man Kim; Zee Won Lee; Sung Jae Shin; Heekyung Yoo; Young Kil Park; Jin Bong Park; Jongkyeong Chung; Tamotsu Yoshimori; Eun Kyeong Jo

doi:10.1016/j.chom.2012.03.008

Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. © 2012 Elsevier Inc.

Jwa Jin Kim, Hye Mi Lee, Dong Min Shin, Wonho Kim, Jae Min Yuk, Hyo Sun Jin, Sang Hee Lee, Guang Ho Cha, Jin Man Kim, Zee Won Lee, Sung Jae Shin, Heekyung Yoo, Young Kil Park, Jin Bong Park, Jongkyeong Chung, Tamotsu Yoshimori, Eun Kyeong Jo

Department of Microbiology

Research output: Contribution to journal › Article › peer-review

179 Citations (Scopus)

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	https://doi.org/10.1016/j.chom.2012.03.008
Publication status	Published - 2012 May 17

Bibliographical note

Funding 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

Parasitology
Microbiology
Virology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chom.2012.03.008

Cite this

Kim, J. J., Lee, H. M., Shin, D. M., Kim, W., Yuk, J. M., Jin, H. S., Lee, S. H., Cha, G. H., Kim, J. M., Lee, Z. W., Shin, S. J., Yoo, H., Park, Y. K., Park, J. B., Chung, J., Yoshimori, T., & Jo, E. K. (2012). Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. © 2012 Elsevier Inc. Cell Host and Microbe, 11(5), 457-468. https://doi.org/10.1016/j.chom.2012.03.008

@article{0a7e41a14b264c6db1a5de177b686cdd,

title = "Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. {\textcopyright} 2012 Elsevier Inc.",

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.",

author = "Kim, {Jwa Jin} and Lee, {Hye Mi} and Shin, {Dong Min} and Wonho Kim and Yuk, {Jae Min} and Jin, {Hyo Sun} and Lee, {Sang Hee} and Cha, {Guang Ho} and Kim, {Jin Man} and Lee, {Zee Won} and Shin, {Sung Jae} and Heekyung Yoo and Park, {Young Kil} and Park, {Jin Bong} and Jongkyeong Chung and Tamotsu Yoshimori and Jo, {Eun Kyeong}",

note = "Funding 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. ",

year = "2012",

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doi = "10.1016/j.chom.2012.03.008",

language = "English",

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Kim, JJ, Lee, HM, Shin, DM, Kim, W, Yuk, JM, Jin, HS, Lee, SH, Cha, GH, Kim, JM, Lee, ZW, Shin, SJ, Yoo, H, Park, YK, Park, JB, Chung, J, Yoshimori, T & Jo, EK 2012, 'Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. © 2012 Elsevier Inc.', Cell Host and Microbe, vol. 11, no. 5, pp. 457-468. https://doi.org/10.1016/j.chom.2012.03.008

TY - JOUR

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

N1 - Funding 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.

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.

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AN - SCOPUS:84861180818

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JO - Cell Host and Microbe

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Host cell autophagy activated by antibiotics is required for their effective antimycobacterial drug action. © 2012 Elsevier Inc.

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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