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  • Review Article
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Carbon metabolism of intracellular bacterial pathogens and possible links to virulence

Nature Reviews Microbiology volume 8, pages 401–412 (2010)Cite this article

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Key Points

  • Recent progress has expanded our knowledge about the metabolism of the model bacterial pathogens Listeria monocytogenes, Shigella flexneri (and the closely related enteroinvasive Escherichia coli (EIEC)), Salmonella enterica subsp. enterica serovar Typhimurium and Mycobacterium tuberculosis when living inside the host cell.

  • Differences in the metabolic characteristics of these four pathogens have been elucidated in the context of the metabolism of host cell lines used for in vitro infection.

  • There are several tools available to study the metabolism of these intracellular pathogens, and differential gene expression profiling (DGEP) and 13C isotopologue analysis (13C-IPA) have been particularly fruitful; however, there are both strengths and weaknesses for these techniques.

  • Models have been suggested (mainly on the basis of data from DGEP and 13C-IPA studies) for the metabolic pathways and fluxes used by the four pathogens when replicating in their specific intracellular compartments (the cytosol or specific phagosomal vacuoles of the host cell). Each pathogen adapts specifically to the host cell environment but exhibits a surprisingly high metabolic flexibility in response to altered metabolic conditions.

  • There is limited experimental evidence for interference by the metabolism of these intracellular bacteria with the expression of virulence genes that are required for their intracellular lifestyles.

  • There is an urgent need for improved in vivo systems and more sensitive analytical tools for studying the metabolism of the bacterial pathogens in real target cells and animal models.

Abstract

New technologies such as high-throughput methods and 13C-isotopologue-profiling analysis are beginning to provide us with insight into the in vivo metabolism of microorganisms, especially in the host cell compartments that are colonized by intracellular bacterial pathogens. In this Review, we discuss the recent progress made in determining the major carbon sources and metabolic pathways used by model intracellular bacterial pathogens that replicate either in the cytosol or in vacuoles of infected host cells. Furthermore, we highlight the possible links between intracellular carbon metabolism and the expression of virulence genes.

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Figure 1: Metabolic pathways of typical heterotrophic and prototrophic bacteria.
Figure 2: Overview of the metabolic dependency of the four bacterial pathogens on host cell nutrients.
Figure 3: Models for the intracellular metabolism of Listeria monocytogenes and enteroinvasive Escherichia coli.
Figure 4: Models for the intracellular metabolism of Salmonella enterica subsp. enterica serovar Typhimurium and Mycobacterium tuberculosis.

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Acknowledgements

Work in the authors' laboratories is supported by grants from the German Research Foundation (DFG) (including grant numbers SPP1316, SFB479 and TR34). We thank E. Eylert for valuable suggestions and editorial help, and for allowing us to cite unpublished results. We thank A. Bacher, R. Gross and R. Haas for critical reading of the manuscript.

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Authors and Affiliations

  1. Lehrstuhl für Biochemie, Technische Universität München, D-85747, Garching, Germany

    Wolfgang Eisenreich

  2. Biocenter (Bioinformatics), University of Würzburg,

    Thomas Dandekar

  3. Max von Pettenkofer-Institut, Ludwig-Maximilians-Universität München, D-80090, München, Germany

    Jürgen Heesemann & Werner Goebel

  4. Biocenter (Microbiology), University of Würzburg, D-97074, Würzburg, Germany

    Werner Goebel

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  1. Wolfgang Eisenreich
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Supplementary information

Supplementary information S1 (figure)

DGEP data compiled from published reports1,2, showing the Listeria monocytogenes genes encoding enzymes involved in the central metabolic pathways that are up-or down-regulated in L. monocytogenes grown in J774 macrophages and in BHI culture medium (up-regulated genes are marked with red and down-regulated ones with green arrows, respectively; blue arrows indicate non-differentially expressed genes. (PDF 189 kb)

Supplementary information S2 (figure)

a | DGEP data3 obtained with RNA derived from S. flexneri grown in U937 macrophages (numbers refer to RNA expression values after normalization) compared to RNA derived from S. flexneri grown in LB medium (for further details see3). b | DGEP data1 obtained with RNA derived from S. flexneri grown in HeLa cells (green numbers) compared to RNA derived from S. flexneri grown in LB medium (for further details see1). Up–regulated genes are indicated by red arrows and down–regulated ones by green arrows; blue arrows indicate non–differentially expressed genes. (PDF 201 kb)

Supplementary information S3 (figure)

a | DGEP data compiled from published report1, showing the up-and down-regulated genes, coding for enzymes involved in the central metabolic pathways of S. Typhimurium grown in J774 macrophages compared to RNA derived from S. Typhimurium grown in LB medium (for further details see1). b | DGEP data compiled from published report1, showing the up-and down-regulated genes, coding for enzymes involved in the central metabolic pathways of S. Typhimurium grown in J774 macrophages compared to RNA derived from S. Typhimurium grown in RPMI medium with glucose; for further details see1. Up–regulated genes are indicated by red arrows and down-regulated by green arrows, respectively; blue arrows indicate non–differentially expressed genes. Note that DGEF values in part b are dramatically different from those in part a for several genes. (PDF 208 kb)

Supplementary information S4 (figure)

DGEP data compiled from the published report5, showing the up-and down-regulated genes, coding for enzymes involved in the central metabolic pathways of M. tuberculosis. (PDF 193 kb)

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DATABASES

Entrez Genome Project

Listeria monocytogenes

Mycobacterium bovis bacille Calmette–Guérin

Mycobacterium tuberculosis

Salmonella enterica subsp. enterica serovar Typhimurium

Shigella flexneri

FURTHER INFORMATION

Werner Goebel's homepage

Glossary

Heterotroph

An organism that uses organic carbon compounds as energy sources and substrates for all carbon intermediates.

Granuloma

A ball-shaped assembly of mononuclear cells that is formed when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate.

Prototrophic

The ability of an organism to synthesize all the essential organic compounds required for its growth itself.

Anapleurotic reaction

A reaction that replenishes intermediates of the central metabolic pathways.

Glyoxylate shunt

An anapleurotic pathway from some bacteria (and some higher plants), involving isocitrate lyase and malate synthase, which together convert isocitrate of the TCA cycle to malate or oxaloacetate.

Anaerobiosis

The production of energy by an organism without the involvement of oxygen.

Isotopologue

A molecular species that differs from another only in containing one or more heavier atoms (owing to these atoms having a different number of neutrons).

Pathogenicity island

A discrete genetic unit (with a distinct GC content and a size ranging from 10 to 200 kb) in bacteria, often flanked by direct repeats and often inserted into tRNA genes. These islands usually carry genes that contribute to the virulence of the respective pathogen.

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Eisenreich, W., Dandekar, T., Heesemann, J. et al. Carbon metabolism of intracellular bacterial pathogens and possible links to virulence. Nat Rev Microbiol 8, 401–412 (2010). https://doi.org/10.1038/nrmicro2351

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