PMID- 31201418
OWN - NLM
STAT- MEDLINE
DCOM- 20200415
LR  - 20200415
IS  - 1460-2377 (Electronic)
IS  - 0953-8178 (Print)
IS  - 0953-8178 (Linking)
VI  - 31
IP  - 12
DP  - 2019 Nov 8
TI  - Metabolic adaptation to glycolysis is a basic defense mechanism of macrophages 
      for Mycobacterium tuberculosis infection.
PG  - 781-793
LID - 10.1093/intimm/dxz048 [doi]
AB  - 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-1alpha (HIF-1alpha) in TB granulomas and more rapid death of HIF-1alpha-conditional 
      knockout mice than wild-type (WT) mice after M. tuberculosis infection. Although 
      interferon-gamma (IFN-gamma) is a critical host-protective cytokine against intracellular 
      pathogens, HIF-1-deficient macrophages permitted M. tuberculosis growth even 
      after activation with IFN-gamma. These results prompted us to investigate the role of 
      HIF-1alpha in host defenses against infection. We found that the expression of 
      lactate dehydrogenase-A (LDH-A) was controlled by HIF-1alpha in M. 
      tuberculosis-infected macrophages IFN-gamma independently. LDH-A is an enzyme that 
      converts pyruvate to lactate and we found that the intracellular level of 
      pyruvate in HIF-1alpha-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-1alpha prevents the 
      hijacking of pyruvate in macrophages, making it a fundamental host-protective 
      mechanism against M. tuberculosis.
CI  - (c) The Author(s) 2019. Published by Oxford University Press on behalf of The 
      Japanese Society for Immunology.
FAU - Osada-Oka, Mayuko
AU  - Osada-Oka M
AD  - Food Hygiene and Environmental Health, Graduate School of Life and Environmental 
      Science, Kyoto Prefectural University, Kyoto, Kyoto, Japan.
FAU - Goda, Nobuhito
AU  - Goda N
AD  - Department of Life Science and Medical BioScience, Waseda University School of 
      Advanced Science and Engineering, Shinjuku-ku, Tokyo, Japan.
FAU - Saiga, Hiroyuki
AU  - Saiga H
AD  - Department of Microbiology and Immunology, Graduate School of Medicine, Osaka 
      University, Suita, Osaka, Japan.
FAU - Yamamoto, Masahiro
AU  - Yamamoto M
AD  - Department of Microbiology and Immunology, Graduate School of Medicine, Osaka 
      University, Suita, Osaka, Japan.
FAU - Takeda, Kiyoshi
AU  - Takeda K
AD  - Department of Microbiology and Immunology, Graduate School of Medicine, Osaka 
      University, Suita, Osaka, Japan.
FAU - Ozeki, Yuriko
AU  - Ozeki Y
AD  - Department of Bacteriology, Niigata University Graduate School of Medical and 
      Dental Sciences, Niigata, Niigata, Japan.
FAU - Yamaguchi, Takehiro
AU  - Yamaguchi T
AD  - Department of Bacteriology, Niigata University Graduate School of Medical and 
      Dental Sciences, Niigata, Niigata, Japan.
FAU - Soga, Tomoyoshi
AU  - Soga T
AD  - Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
FAU - Tateishi, Yu
AU  - Tateishi Y
AD  - Department of Applied Pharmacology and Therapeutics, Osaka City University 
      Graduate School of Medicine, Osaka, Osaka, Japan.
FAU - Miura, Katsuyuki
AU  - Miura K
AD  - Department of Applied Pharmacology and Therapeutics, Osaka City University 
      Graduate School of Medicine, Osaka, Osaka, Japan.
FAU - Okuzaki, Daisuke
AU  - Okuzaki D
AD  - Genome Information Research Center, Research Institute for Microbial Diseases, 
      Osaka University, Suita, Osaka, Japan.
FAU - Kobayashi, Kazuo
AU  - Kobayashi K
AD  - Division of Public Health, Osaka Institute of Public Health, Osaka, Osaka, Japan.
FAU - Matsumoto, Sohkichi
AU  - Matsumoto S
AD  - Department of Bacteriology, Niigata University Graduate School of Medical and 
      Dental Sciences, Niigata, Niigata, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Int Immunol
JT  - International immunology
JID - 8916182
RN  - 0 (Homeodomain Proteins)
RN  - 128559-51-3 (RAG-1 protein)
SB  - IM
MH  - Animals
MH  - *Glycolysis
MH  - Homeodomain Proteins/metabolism
MH  - Macrophages/*metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mycobacterium tuberculosis/metabolism
MH  - Tuberculosis/*metabolism
PMC - PMC6839748
OTO - NOTNLM
OT  - granuloma
OT  - hypoxia-inducible factor-1alpha
OT  - pyruvate
OT  - tuberculosis
EDAT- 2019/06/16 06:00
MHDA- 2020/04/16 06:00
PMCR- 2019/06/14
CRDT- 2019/06/16 06:00
PHST- 2018/11/12 00:00 [received]
PHST- 2019/06/26 00:00 [accepted]
PHST- 2019/06/16 06:00 [pubmed]
PHST- 2020/04/16 06:00 [medline]
PHST- 2019/06/16 06:00 [entrez]
PHST- 2019/06/14 00:00 [pmc-release]
AID - 5519316 [pii]
AID - dxz048 [pii]
AID - 10.1093/intimm/dxz048 [doi]
PST - ppublish
SO  - Int Immunol. 2019 Nov 8;31(12):781-793. doi: 10.1093/intimm/dxz048.