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Carbon flux rerouting during Mycobacterium tuberculosis growth arrest.
Mol Microbiol. 2010 Dec; 78(5):1199-215
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14 Jan 2011
DOI: 10.3410/f.7498958.7793056
This excellent paper changes our current view of how Mycobacterium tuberculosis adapts to a metabolic dormant state. The previous idea of bacilli readjusting metabolism as a consequence of changes in nutrient availability (thought to be mainly fatty acids during the persistence phase), does not reconcile...Continue reading
This excellent paper changes our current view of how Mycobacterium tuberculosis adapts to a metabolic dormant state. The previous idea of bacilli readjusting metabolism as a consequence of changes in nutrient availability (thought to be mainly fatty acids during the persistence phase), does not reconcile with the data presented in this study. Instead, it supports the existence of a developmental program triggered by the bacilli upon growth arrest.
The authors first analyze in vivo gene expression data of key M. tuberculosis metabolic genes infecting mice in a model in which bacteria undergo two well-defined phases: an early active growth period followed by stabilization of bacterial numbers caused by the host immune response. These transcriptional data, collected from 10 to 100 days post-infection, are further compared to in silico metabolic simulations of bacilli in either growing or non-growing states, and to transcriptional data obtained from bacilli cultured in vitro under stress conditions impairing active growth (hypoxia, nitric oxide [NO] exposure). The comparisons favour a metabolic shift under growth arrest, with clear signatures such as the generation of the C3 compounds phosphoenol-pyruvate (PEP) and pyruvate and the accumulation of storage compounds as triacylglycerol (TAG) and glutamate. Elegant experiments in which the authors use defined medium lacking fatty acids in conditions inducing growth arrest (NO exposure) demonstrate, in essence, similar metabolic changes. This observation evidences that it is the growth arrest, and not the availability of concrete nutrients, which determines such metabolic reprogramming. Similar results were also obtained using modelling of metabolic fluxes in growing and non-growing bacilli exposed to different carbon sources (glucose, phospholipids, or a mix of both). A future challenge will be to dissect the exact bacterial processes targeted by the host defences that culminate in M. tuberculosis growth arrest, and that make the pathogen program this metabolic readjustment.
The authors first analyze in vivo gene expression data of key M. tuberculosis metabolic genes infecting mice in a model in which bacteria undergo two well-defined phases: an early active growth period followed by stabilization of bacterial numbers caused by the host immune response. These transcriptional data, collected from 10 to 100 days post-infection, are further compared to in silico metabolic simulations of bacilli in either growing or non-growing states, and to transcriptional data obtained from bacilli cultured in vitro under stress conditions impairing active growth (hypoxia, nitric oxide [NO] exposure). The comparisons favour a metabolic shift under growth arrest, with clear signatures such as the generation of the C3 compounds phosphoenol-pyruvate (PEP) and pyruvate and the accumulation of storage compounds as triacylglycerol (TAG) and glutamate. Elegant experiments in which the authors use defined medium lacking fatty acids in conditions inducing growth arrest (NO exposure) demonstrate, in essence, similar metabolic changes. This observation evidences that it is the growth arrest, and not the availability of concrete nutrients, which determines such metabolic reprogramming. Similar results were also obtained using modelling of metabolic fluxes in growing and non-growing bacilli exposed to different carbon sources (glucose, phospholipids, or a mix of both). A future challenge will be to dissect the exact bacterial processes targeted by the host defences that culminate in M. tuberculosis growth arrest, and that make the pathogen program this metabolic readjustment.
Disclosures
None declared
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Garcia-del Portillo F: F1000Prime Recommendation of [Shi L et al., Mol Microbiol 2010, 78(5):1199-215]. In F1000Prime, 14 Jan 2011; DOI: 10.3410/f.7498958.7793056. F1000Prime.com/7498958#eval7793056
F1000Prime Recommendations, Dissents and Comments for [Shi L et al., Mol Microbiol 2010, 78(5):1199-215]. In F1000Prime, 23 May 2013; F1000Prime.com/7498958
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A hallmark of the Mycobacterium tuberculosis life cycle is the pathogen's ability to switch between replicative and non-replicative states in response to host immunity. Transcriptional profiling by qPCR of ∼ 50 M. tuberculosis genes involved in central and lipid metabolism revealed a re-routing of carbon flow associated with bacterial growth arrest during mouse lung infection. Carbon rerouting was marked by a switch from metabolic pathways generating energy and biosynthetic precursors in growing bacilli to pathways for storage compound synthesis during growth arrest. Results of flux balance analysis using an in silico metabolic network were consistent with the transcript abundance data obtained in vivo. Similar transcriptional changes were seen in vitro when M. tuberculosis cultures were treated with bacteriostatic stressors under different nutritional conditions. Thus, altered expression of key metabolic genes reflects growth rate changes rather than changes in substrate availability. A model describing carbon flux rerouting was formulated that (i) provides a coherent interpretation of the adaptation of M. tuberculosis metabolism to immunity-induced stress and (ii) identifies features common to mycobacterial dormancy and stress responses of other organisms.
DOI: 10.1111/j.1365-2958.2010.07399.x
PMID: 21091505
