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...

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Autores principales:	Michael Zimmermann, Maria Kogadeeva, Martin Gengenbacher, Gayle McEwen, Hans-Joachim Mollenkopf, Nicola Zamboni, Stefan Hugo Ernst Kaufmann, Uwe Sauer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Mycobacterium tuberculosis host-pathogen interactions metabolism systems biology Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cfb445e88e4d4cf48d220a6311bbdad6
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spelling	oai:doaj.org-article:cfb445e88e4d4cf48d220a6311bbdad62021-12-02T18:39:33ZIntegration of Metabolomics and Transcriptomics Reveals a Complex Diet of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> during Early Macrophage Infection10.1128/mSystems.00057-172379-5077https://doaj.org/article/cfb445e88e4d4cf48d220a6311bbdad62017-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00057-17https://doaj.org/toc/2379-5077ABSTRACT 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.Michael ZimmermannMaria KogadeevaMartin GengenbacherGayle McEwenHans-Joachim MollenkopfNicola ZamboniStefan Hugo Ernst KaufmannUwe SauerAmerican Society for MicrobiologyarticleMycobacterium tuberculosishost-pathogen interactionsmetabolismsystems biologyMicrobiologyQR1-502ENmSystems, Vol 2, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mycobacterium tuberculosis host-pathogen interactions metabolism systems biology Microbiology QR1-502
spellingShingle	Mycobacterium tuberculosis host-pathogen interactions metabolism systems biology Microbiology QR1-502 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
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.
format	article
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
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_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_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_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
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/cfb445e88e4d4cf48d220a6311bbdad6
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Integration of Metabolomics and Transcriptomics Reveals a Complex Diet of <named-content content-type="genus-species">Mycobacterium tuberculosis</named-content> during Early Macrophage Infection

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