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Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection

Macrophages are major components of tuberculosis (TB) granulomas and are responsible for host defenses against the intracellular pathogen, Mycobacterium tuberculosis. We herein showed the strong expression of hypoxia-inducible factor-1α (HIF-1α) in TB granulomas and more rapid death of HIF-1α-condit...

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Autores principales: Osada-Oka, Mayuko, Goda, Nobuhito, Saiga, Hiroyuki, Yamamoto, Masahiro, Takeda, Kiyoshi, Ozeki, Yuriko, Yamaguchi, Takehiro, Soga, Tomoyoshi, Tateishi, Yu, Miura, Katsuyuki, Okuzaki, Daisuke, Kobayashi, Kazuo, Matsumoto, Sohkichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839748/
https://www.ncbi.nlm.nih.gov/pubmed/31201418
http://dx.doi.org/10.1093/intimm/dxz048
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author Osada-Oka, Mayuko
Goda, Nobuhito
Saiga, Hiroyuki
Yamamoto, Masahiro
Takeda, Kiyoshi
Ozeki, Yuriko
Yamaguchi, Takehiro
Soga, Tomoyoshi
Tateishi, Yu
Miura, Katsuyuki
Okuzaki, Daisuke
Kobayashi, Kazuo
Matsumoto, Sohkichi
author_facet Osada-Oka, Mayuko
Goda, Nobuhito
Saiga, Hiroyuki
Yamamoto, Masahiro
Takeda, Kiyoshi
Ozeki, Yuriko
Yamaguchi, Takehiro
Soga, Tomoyoshi
Tateishi, Yu
Miura, Katsuyuki
Okuzaki, Daisuke
Kobayashi, Kazuo
Matsumoto, Sohkichi
author_sort Osada-Oka, Mayuko
collection PubMed
description Macrophages are major components of tuberculosis (TB) granulomas and are responsible for host defenses against the intracellular pathogen, Mycobacterium tuberculosis. We herein showed the strong expression of hypoxia-inducible factor-1α (HIF-1α) in TB granulomas and more rapid death of HIF-1α-conditional knockout mice than wild-type (WT) mice after M. tuberculosis infection. Although interferon-γ (IFN-γ) is a critical host-protective cytokine against intracellular pathogens, HIF-1-deficient macrophages permitted M. tuberculosis growth even after activation with IFN-γ. These results prompted us to investigate the role of HIF-1α in host defenses against infection. We found that the expression of lactate dehydrogenase-A (LDH-A) was controlled by HIF-1α in M. tuberculosis-infected macrophages IFN-γ independently. LDH-A is an enzyme that converts pyruvate to lactate and we found that the intracellular level of pyruvate in HIF-1α-deficient bone marrow-derived macrophages (BMDMs) was significantly higher than in WT BMDMs. Intracellular bacillus replication was enhanced by an increase in intracellular pyruvate concentrations, which were decreased by LDH-A. Mycobacteria in phagosomes took up exogenous pyruvate more efficiently than glucose, and used it as the feasible carbon source for intracellular growth. These results demonstrate that HIF-1α prevents the hijacking of pyruvate in macrophages, making it a fundamental host-protective mechanism against M. tuberculosis.
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spelling pubmed-68397482019-11-14 Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection Osada-Oka, Mayuko Goda, Nobuhito Saiga, Hiroyuki Yamamoto, Masahiro Takeda, Kiyoshi Ozeki, Yuriko Yamaguchi, Takehiro Soga, Tomoyoshi Tateishi, Yu Miura, Katsuyuki Okuzaki, Daisuke Kobayashi, Kazuo Matsumoto, Sohkichi Int Immunol Original Research Macrophages are major components of tuberculosis (TB) granulomas and are responsible for host defenses against the intracellular pathogen, Mycobacterium tuberculosis. We herein showed the strong expression of hypoxia-inducible factor-1α (HIF-1α) in TB granulomas and more rapid death of HIF-1α-conditional knockout mice than wild-type (WT) mice after M. tuberculosis infection. Although interferon-γ (IFN-γ) is a critical host-protective cytokine against intracellular pathogens, HIF-1-deficient macrophages permitted M. tuberculosis growth even after activation with IFN-γ. These results prompted us to investigate the role of HIF-1α in host defenses against infection. We found that the expression of lactate dehydrogenase-A (LDH-A) was controlled by HIF-1α in M. tuberculosis-infected macrophages IFN-γ independently. LDH-A is an enzyme that converts pyruvate to lactate and we found that the intracellular level of pyruvate in HIF-1α-deficient bone marrow-derived macrophages (BMDMs) was significantly higher than in WT BMDMs. Intracellular bacillus replication was enhanced by an increase in intracellular pyruvate concentrations, which were decreased by LDH-A. Mycobacteria in phagosomes took up exogenous pyruvate more efficiently than glucose, and used it as the feasible carbon source for intracellular growth. These results demonstrate that HIF-1α prevents the hijacking of pyruvate in macrophages, making it a fundamental host-protective mechanism against M. tuberculosis. Oxford University Press 2019-06-14 /pmc/articles/PMC6839748/ /pubmed/31201418 http://dx.doi.org/10.1093/intimm/dxz048 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of The Japanese Society for Immunology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Research
Osada-Oka, Mayuko
Goda, Nobuhito
Saiga, Hiroyuki
Yamamoto, Masahiro
Takeda, Kiyoshi
Ozeki, Yuriko
Yamaguchi, Takehiro
Soga, Tomoyoshi
Tateishi, Yu
Miura, Katsuyuki
Okuzaki, Daisuke
Kobayashi, Kazuo
Matsumoto, Sohkichi
Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection
title Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection
title_full Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection
title_fullStr Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection
title_full_unstemmed Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection
title_short Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection
title_sort metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for mycobacterium tuberculosis infection
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839748/
https://www.ncbi.nlm.nih.gov/pubmed/31201418
http://dx.doi.org/10.1093/intimm/dxz048
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