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Metabolic anticipation in Mycobacterium tuberculosis

Nature Microbiology volume 2, Article number: 17084 (2017) Cite this article

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Abstract

Humans serve as both host and reservoir for Mycobacterium tuberculosis, making tuberculosis a theoretically eradicable disease. How M. tuberculosis alternates between host-imposed quiescence and sporadic bouts of replication to complete its life cycle, however, remains unknown. Here, we identify a metabolic adaptation that is triggered upon entry into hypoxia-induced quiescence but facilitates subsequent cell cycle re-entry. Catabolic remodelling of the cell surface trehalose mycolates of M. tuberculosis specifically generates metabolic intermediates reserved for re-initiation of peptidoglycan biosynthesis. These adaptations reveal a metabolic network with the regulatory capacity to mount an anticipatory response.

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Figure 1: Hypoxia induces remodelling of upper glycolysis, amino sugar and nucleotide sugar biosynthesis and pentose phosphate pathways in M. tuberculosis.
Figure 2: Hypoxia induces selective alterations in M. tuberculosis cell envelope lipid levels and immunoreactivity.
Figure 3: Biochemical essentiality of TreS in hypoxia-triggered anticipatory metabolic remodelling of M. tuberculosis.
Figure 4: Biochemical shunting of hypoxia-induced metabolic stores into de novo peptidoglycan biosynthesis during re-aeration.

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Acknowledgements

The authors thank G. Rehren and D. Schnappinger for advice in constructing knockout strains, C. Nathan, J. Vaubourgeix, S. Ehrt and S. Tavazoie for critical discussions and reading of the manuscript, S. Fischer for expert mass spectrometric support and the Bill and Melinda Gates Foundation Grand Challenges Exploration Program (OPP1068025) and National Institutes of Health Tri-I TBRU (U19-AI11143) for support.

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Author notes

  1. Hyungjin Eoh

    Present address: Department of Molecular Microbiology & Immunology, Keck School of Medicine, ZNI 537 1501 San Pablo, Los Angeles, California, 90033, USA

  2. Emilie Layre

    Present address: National Center for Scientific Research, Institute of Pharmacology & Structural Biology, 205 route de Narbonne, BP64182, Toulouse, 31077, France

Authors and Affiliations

  1. Division of Infectious Diseases, Weill Department of Medicine, Weill Cornell Medical College, New York, 10065, New York, USA

    Hyungjin Eoh, Zhe Wang, Roxanne Morris & Kyu Y. Rhee

  2. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Emilie Layre & D. Branch Moody

  3. Department of Microbiology & Immunology, Weill Cornell Medical College, New York, 10065, New York, USA

    Poonam Rath & Kyu Y. Rhee

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Contributions

H.E. and Z.W. designed, conducted and analysed metabolomic profiling studies. E.L. and D.B.M. conducted and analysed lipidomic profiling studies. H.E. and P.R. conducted macrophage cytokine release assays. H.E., Z.W. and R.M. conducted antibiotic susceptibility assays. K.Y.R. initiated and directed this research.

Corresponding author

Correspondence to Kyu Y. Rhee.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures 1–8. (PDF 1539 kb)

Supplementary Data 1

All relevant source data related to metabolomic and lipidomic data shown in Figures 1–4 and Supplementary Figures 1–8. (XLSX 103 kb)

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Eoh, H., Wang, Z., Layre, E. et al. Metabolic anticipation in Mycobacterium tuberculosis. Nat Microbiol 2, 17084 (2017). https://doi.org/10.1038/nmicrobiol.2017.84

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