Dataset Information

Metabolism of host-derived glycolytic products by Mycobacterium tuberculosis requires five metabolic pathways

ABSTRACT: Bacterial nutrition is a key aspect of host-pathogen interaction and bacteria must adapt to use nutrients available in the host. Lipid droplets-derived fatty acids are considered the major intracellular carbon source for Mycobacterium tuberculosis (Mtb), an intracellular pathogen causing Tuberculosis disease. However, many other (and more soluble) substrates are available in vivo and may represent alternative carbon sources. Lactate and pyruvate are rather abundant in human cells and fluids and represent two possible candidates. In this work, we employed a “multi-omics” approach (Transposon Directed Insertion Site Sequencing (TraDIS), RNA-seq transcriptomics, proteomics and stable isotopic labelling coupled with mass spectrometry-based metabolomics) and classic microbial physiology to study Mtb metabolism of lactate and pyruvate. We discovered that Mtb is well adapted to use lactate and pyruvate as sole carbon sources and that it requires gluconeogenesis, Krebs cycle, GABA shunt, glyoxylate shunt and methylcitrate cycle for their metabolism. These latter are traditionally associated with fatty acid metabolism and unexpectedly, we found that methylcitrate cycle operates in reverse. This latter discovery changes the role of this pathway making it a direct route for the biosynthesis of propionyl-CoA, the essential precursor for the biosynthesis of odd-chain fatty acids, abundantly present in Mtb cell envelope.

OTHER RELATED OMICS DATASETS IN: GSE116859

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mycobacterium Tuberculosis H37rv

SUBMITTER: Steven Howell

LAB HEAD: Bram Snijders

PROVIDER: PXD010726 | Pride | 2020-05-26

REPOSITORIES: Pride

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Publications

Mycobacterium tuberculosis requires glyoxylate shunt and reverse methylcitrate cycle for lactate and pyruvate metabolism.

Serafini Agnese A Tan Lendl L Horswell Stuart S Howell Steven S Greenwood Daniel J DJ Hunt Deborah M DM Phan Minh-Duy MD Schembri Mark M Monteleone Mercedes M Montague Christine R CR Britton Warwick W Garza-Garcia Acely A Snijders Ambrosius P AP VanderVen Brian B Gutierrez Maximiliano G MG West Nicholas P NP de Carvalho Luiz Pedro S LPS

Molecular microbiology 20190823 4

Bacterial nutrition is an essential aspect of host-pathogen interaction. For the intracellular pathogen Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans, fatty acids derived from lipid droplets are considered the major carbon source. However, many other soluble nutrients are available inside host cells and may be used as alternative carbon sources. Lactate and pyruvate are abundant in human cells and fluids, particularly during inflammation. In this work, we study ...[more]

PMID: 31389636

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Project description:The capacity of Mycobacterium tuberculosis (Mtb) to sense, respond and adapt to variable and hostile environment within the host, has made it one of the most successful human pathogens. During different stages of infection, the bacillus is surrounding by a plethora of lipid rich molecules and current evidence points out the relevance of fatty acids during the Mtb infectious process. In this study, we have compared the transcriptional response of Mtb to hypoxia in cultures grown in both, a mix of even long-chain fatty acids and dextrose as carbon sources. Using RNA sequencing, we have identified the differential expressed genes in early and late hypoxia defined according to the in vitro Wayne model and compared the results with the exponential phase of growth in both carbon sources. Our results showed that, different to dextrose, the number of genes overexpressed in hypoxia in the lipid medium was quite low in both, early and late hypoxia in all functional categories describes for Mtb. The exception were the transcripts of stable and non-coding RNAs which were more expressed in the fatty acid medium. We found that SigB and SigE were overexpressed in the early phase of hypoxia, confirming their pivotal role in early adaptation to low oxygen concentration independently of the carbon source. A drastic contrast was found with the transcriptional regulatory factors at early hypoxia. Only 2 transcriptional factors were overexpressed in early hypoxia in the lipid medium compared to 37 that were overexpressed in the dextrose medium. Instead of Rv0081, known to be the central regulator of hypoxia in dextrose, Rv2745c, (ClgR), is playing a main role in hypoxia in the fatty acids medium. The low level of genes associated to stress-response, showed by Mtb during their adaptation to hypoxia in fatty acids, suggested that this lipid environment makes hypoxia a less stressful condition for the tubercle bacilli. Therefore, when the bacillus is surviving in that environment, its metabolism seemed to be already adapted to different stresses within the host, including hypoxia. This fact could explain the success of Mtb to establish long-term survival during latent infection.

Dataset Information

Metabolism of host-derived glycolytic products by Mycobacterium tuberculosis requires five metabolic pathways

Publications

Mycobacterium tuberculosis requires glyoxylate shunt and reverse methylcitrate cycle for lactate and pyruvate metabolism.

Similar Datasets

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