Salmonella modulates metabolism during growth under conditions that induce expression of virulence genes

Abstract

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative pathogen that uses complex mechanisms to invade and proliferate within mammalian host cells. To investigate possible contributions of metabolic processes to virulence in S. Typhimurium grown under conditions known to induce expression of virulence genes, we used a metabolomics-driven systems biology approach coupled with genome scale modeling. First, we identified distinct metabolite profiles associated with bacteria grown in either rich or virulence-inducing media and report the most comprehensive coverage of the S. Typhimurium metabolome to date. Second, we applied an omics-informed genome scale modeling analysis of the functional consequences of adaptive alterations in S. Typhimurium metabolism during growth under our conditions. Modeling efforts highlighted a decreased cellular capability to both produce and utilize intracellular amino acids during stationary phase culture in virulence conditions, despite significant abundance increases for these molecules as observed by our metabolomics measurements. Furthermore, analyses of omics data in the context of the metabolic model indicated rewiring of the metabolic network to support pathways associated with virulence. For example, cellular concentrations of polyamines were perturbed, as well as the predicted capacity for secretion and uptake.

Bacterial peptide transporters: Messengers of nutrition to virulence

“…9 Salmonella is even known to modulate host to exploit the limited supply of nutrients. 8,12 Coupling of nutrition with virulence reveals metabolism associated genes that can be targeted for antimicrobial therapy. Peptide transporters represent one such class of genes known to be required for virulence of Gram negative as well as Gram positive pathogens.…”

“…61 The stationary growth phase dependent expression of virulence factors is accompanied by decrease in amino acid biosynthesis. 12 However, the concentration of amino acids is maintained in the stationary phase as well as during the later stage of infection inside host cell. 12 This suggests parallel import of amino acids or peptides containing the required amino acids.…”

“…12 However, the concentration of amino acids is maintained in the stationary phase as well as during the later stage of infection inside host cell. 12 This suggests parallel import of amino acids or peptides containing the required amino acids. Hence, peptide transporters of Salmonella may provide for the amino acids required for survival inside host and thereby play a role in the establishment of infection.…”

Silymarin suppresses cellular inflammation by inducing reparative stress signaling

“…Metabolites were extracted using chloroform/methanol (2:1 v/v) and chemically derivatized for analysis by gas chromatography-mass spectrometry (GC-MS), as previously described. [69][70][71] An Agilent 7890A gas chromatograph coupled with a single quadrupole 5975C mass spectrometer (Agilent Technologies, Santa Clara, CA) was used for metabolomics analyses, and metabolomics data were processed using MetaboliteDetector, as previously described. [69][70][71][72] The integrated peak areas of identified metabolites were z-score transformed and visualized as a heat-map using InfernoRND (http://omics.pnl.gov/software/infernordn).…”

Salmonella Utilizes D-Glucosaminate via a Mannose Family Phosphotransferase System Permease and Associated Enzymes

“…While a considerable amount of work has focused on elucidating the mechanisms by which Salmonella pathogenicity genes promote infection (2-6), until recently little attention has been paid to understanding the nutritional and metabolic requirements of Salmonella during colonization (7,8). Several recent papers have used "-omics"-driven (i.e., genomics, transcriptomics, proteomics, and metabolomics) systems biology approaches to investigate potential contributions of metabolic processes to Salmonella colonization and/or virulence (9)(10)(11)(12)(13). The utility of such approaches, however, is limited by gaps in our knowledge of metabolic pathways in Salmonella and by dubious or uninformative gene annotations.…”