Integration of Metabolomics and Transcriptomics Reveals a Complex Diet of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> during Early Macrophage Infection
ABSTRACT Nutrient acquisition from the host environment is crucial for the survival of intracellular pathogens, but conceptual and technical challenges limit our knowledge of pathogen diets. To overcome some of these technical roadblocks, we exploited an experimentally accessible model for early inf...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2017-08-01
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| Series: | mSystems |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mSystems.00057-17 |
| _version_ | 1818998341784043520 |
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| author | Michael Zimmermann Maria Kogadeeva Martin Gengenbacher Gayle McEwen Hans-Joachim Mollenkopf Nicola Zamboni Stefan Hugo Ernst Kaufmann Uwe Sauer |
| author_facet | Michael Zimmermann Maria Kogadeeva Martin Gengenbacher Gayle McEwen Hans-Joachim Mollenkopf Nicola Zamboni Stefan Hugo Ernst Kaufmann Uwe Sauer |
| author_sort | Michael Zimmermann |
| collection | DOAJ |
| description | ABSTRACT Nutrient acquisition from the host environment is crucial for the survival of intracellular pathogens, but conceptual and technical challenges limit our knowledge of pathogen diets. To overcome some of these technical roadblocks, we exploited an experimentally accessible model for early infection of human macrophages by Mycobacterium tuberculosis, the etiological agent of tuberculosis, to study host-pathogen interactions with a multi-omics approach. We collected metabolomics and complete transcriptome RNA sequencing (dual RNA-seq) data of the infected macrophages, integrated them in a genome-wide reaction pair network, and identified metabolic subnetworks in host cells and M. tuberculosis that are modularly regulated during infection. Up- and downregulation of these metabolic subnetworks suggested that the pathogen utilizes a wide range of host-derived compounds, concomitant with the measured metabolic and transcriptional changes in both bacteria and host. To quantify metabolic interactions between the host and intracellular pathogen, we used a combined genome-scale model of macrophage and M. tuberculosis metabolism constrained by the dual RNA-seq data. Metabolic flux balance analysis predicted coutilization of a total of 33 different carbon sources and enabled us to distinguish between the pathogen’s substrates directly used as biomass precursors and the ones further metabolized to gain energy or to synthesize building blocks. This multiple-substrate fueling confers high robustness to interventions with the pathogen’s metabolism. The presented approach combining multi-omics data as a starting point to simulate system-wide host-pathogen metabolic interactions is a useful tool to better understand the intracellular lifestyle of pathogens and their metabolic robustness and resistance to metabolic interventions. IMPORTANCE The nutrients consumed by intracellular pathogens are mostly unknown. This is mainly due to the challenge of disentangling host and pathogen metabolism sharing the majority of metabolic pathways and hence metabolites. Here, we investigated the metabolic changes of Mycobacterium tuberculosis, the causative agent of tuberculosis, and its human host cell during early infection. To this aim, we combined gene expression data of both organisms and metabolite changes during the course of infection through integration into a genome-wide metabolic network. This led to the identification of infection-specific metabolic alterations, which we further exploited to model host-pathogen interactions quantitatively by flux balance analysis. These in silico data suggested that tubercle bacilli consume up to 33 different nutrients during early macrophage infection, which the bacteria utilize to generate energy and biomass to establish intracellular growth. Such multisubstrate fueling strategy renders the pathogen’s metabolism robust toward perturbations, such as innate immune responses or antibiotic treatments. |
| first_indexed | 2024-12-20T22:00:00Z |
| format | Article |
| id | doaj.art-cfb445e88e4d4cf48d220a6311bbdad6 |
| institution | Directory Open Access Journal |
| issn | 2379-5077 |
| language | English |
| last_indexed | 2024-12-20T22:00:00Z |
| publishDate | 2017-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSystems |
| spelling | doaj.art-cfb445e88e4d4cf48d220a6311bbdad62022-12-21T19:25:21ZengAmerican Society for MicrobiologymSystems2379-50772017-08-012410.1128/mSystems.00057-17Integration of Metabolomics and Transcriptomics Reveals a Complex Diet of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> during Early Macrophage InfectionMichael Zimmermann0Maria Kogadeeva1Martin Gengenbacher2Gayle McEwen3Hans-Joachim Mollenkopf4Nicola Zamboni5Stefan Hugo Ernst Kaufmann6Uwe Sauer7Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, SwitzerlandDepartment of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, SwitzerlandDepartment of Immunology, Max Planck Institute for Infection Biology, Berlin, GermanyDepartment of Immunology, Max Planck Institute for Infection Biology, Berlin, GermanyCore Facility Microarray/Genomics, Max Planck Institute for Infection Biology, Berlin, GermanyDepartment of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, SwitzerlandDepartment of Immunology, Max Planck Institute for Infection Biology, Berlin, GermanyDepartment of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, SwitzerlandABSTRACT Nutrient acquisition from the host environment is crucial for the survival of intracellular pathogens, but conceptual and technical challenges limit our knowledge of pathogen diets. To overcome some of these technical roadblocks, we exploited an experimentally accessible model for early infection of human macrophages by Mycobacterium tuberculosis, the etiological agent of tuberculosis, to study host-pathogen interactions with a multi-omics approach. We collected metabolomics and complete transcriptome RNA sequencing (dual RNA-seq) data of the infected macrophages, integrated them in a genome-wide reaction pair network, and identified metabolic subnetworks in host cells and M. tuberculosis that are modularly regulated during infection. Up- and downregulation of these metabolic subnetworks suggested that the pathogen utilizes a wide range of host-derived compounds, concomitant with the measured metabolic and transcriptional changes in both bacteria and host. To quantify metabolic interactions between the host and intracellular pathogen, we used a combined genome-scale model of macrophage and M. tuberculosis metabolism constrained by the dual RNA-seq data. Metabolic flux balance analysis predicted coutilization of a total of 33 different carbon sources and enabled us to distinguish between the pathogen’s substrates directly used as biomass precursors and the ones further metabolized to gain energy or to synthesize building blocks. This multiple-substrate fueling confers high robustness to interventions with the pathogen’s metabolism. The presented approach combining multi-omics data as a starting point to simulate system-wide host-pathogen metabolic interactions is a useful tool to better understand the intracellular lifestyle of pathogens and their metabolic robustness and resistance to metabolic interventions. IMPORTANCE The nutrients consumed by intracellular pathogens are mostly unknown. This is mainly due to the challenge of disentangling host and pathogen metabolism sharing the majority of metabolic pathways and hence metabolites. Here, we investigated the metabolic changes of Mycobacterium tuberculosis, the causative agent of tuberculosis, and its human host cell during early infection. To this aim, we combined gene expression data of both organisms and metabolite changes during the course of infection through integration into a genome-wide metabolic network. This led to the identification of infection-specific metabolic alterations, which we further exploited to model host-pathogen interactions quantitatively by flux balance analysis. These in silico data suggested that tubercle bacilli consume up to 33 different nutrients during early macrophage infection, which the bacteria utilize to generate energy and biomass to establish intracellular growth. Such multisubstrate fueling strategy renders the pathogen’s metabolism robust toward perturbations, such as innate immune responses or antibiotic treatments.https://journals.asm.org/doi/10.1128/mSystems.00057-17Mycobacterium tuberculosishost-pathogen interactionsmetabolismsystems biology |
| spellingShingle | Michael Zimmermann Maria Kogadeeva Martin Gengenbacher Gayle McEwen Hans-Joachim Mollenkopf Nicola Zamboni Stefan Hugo Ernst Kaufmann Uwe Sauer Integration of Metabolomics and Transcriptomics Reveals a Complex Diet of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> during Early Macrophage Infection mSystems Mycobacterium tuberculosis host-pathogen interactions metabolism systems biology |
| title | Integration of Metabolomics and Transcriptomics Reveals a Complex Diet of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> during Early Macrophage Infection |
| title_full | Integration of Metabolomics and Transcriptomics Reveals a Complex Diet of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> during Early Macrophage Infection |
| title_fullStr | Integration of Metabolomics and Transcriptomics Reveals a Complex Diet of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> during Early Macrophage Infection |
| title_full_unstemmed | Integration of Metabolomics and Transcriptomics Reveals a Complex Diet of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> during Early Macrophage Infection |
| title_short | Integration of Metabolomics and Transcriptomics Reveals a Complex Diet of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> during Early Macrophage Infection |
| title_sort | integration of metabolomics and transcriptomics reveals a complex diet of named content content type genus species mycobacterium tuberculosis named content during early macrophage infection |
| topic | Mycobacterium tuberculosis host-pathogen interactions metabolism systems biology |
| url | https://journals.asm.org/doi/10.1128/mSystems.00057-17 |
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