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 journalArticlepeer-review

9 Citations (Scopus)


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
Issue number12
Publication statusPublished - 2019 Aug 1


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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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