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

Mayuko Osada-Oka, Nobuhito Goda, Hiroyuki Saiga, Masahiro Yamamoto, Kiyoshi Takeda, Yuriko Ozeki, Takehiro Yamaguchi, Tomoyoshi Soga, Yu Tateishi, Katsuyuki Miura, Daisuke Okuzaki, Kazuo Kobayashi, Sohkichi Matsumoto

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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-γindependently. 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.

Original languageEnglish
Pages (from-to)781-793
Number of pages13
JournalInternational Immunology
Volume31
Issue number12
DOIs
Publication statusPublished - 2019 Aug 1

Keywords

  • granuloma
  • hypoxia-inducible factor-1α
  • pyruvate
  • tuberculosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Osada-Oka, M., Goda, N., Saiga, H., Yamamoto, M., Takeda, K., Ozeki, Y., Yamaguchi, T., Soga, T., Tateishi, Y., Miura, K., Okuzaki, D., Kobayashi, K., & Matsumoto, S. (2019). Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages for Mycobacterium tuberculosis infection. International Immunology, 31(12), 781-793. https://doi.org/10.1093/intimm/dxz048