Tn-Seq reveals hidden complexity in the utilization of host-derived glutathione in Francisella tularensis

Ramsey, Kathryn M.; Ledvina, Hannah E.; Tresko, Tenayaann M.; Wandzilak, Jamie; Tower, Catherine A.; Tallo, Thomas; Schramm, Caroline E.; Peterson, S. Brook; Skerrett, Shawn J.; Mougous, Joseph D.; Dove, Simon L.

doi:10.1371/journal.ppat.1008566

Cited by 20 publications

(70 citation statements)

References 73 publications

(143 reference statements)

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“…The genome of F. novicida does not contain a gene coding for any enzyme responsible for the conversion of cystine to cysteine. We and others have previously shown that glutathione (γ-Glutamate-cysteine-glycine or GSH) constituted a major host-derived source of cysteine for intracellular Francisella [53,54]. It should be noted that, in addition to serve as an amino acid source for protein biosynthesis cysteine (and cystine) can also be used as sources of sulfur.…”

Section: Plos Pathogensmentioning

confidence: 99%

The pentose phosphate pathway constitutes a major metabolic hub in pathogenic Francisella

et al. 2021

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Metabolic pathways are now considered as intrinsic virulence attributes of pathogenic bacteria and thus represent potential targets for antibacterial strategies. Here we focused on the role of the pentose phosphate pathway (PPP) and its connections with other metabolic pathways in the pathophysiology of Francisella novicida. The involvement of the PPP in the intracellular life cycle of Francisella was first demonstrated by studying PPP inactivating mutants. Indeed, we observed that inactivation of the tktA, rpiA or rpe genes severely impaired intramacrophage multiplication during the first 24 hours. However, time-lapse video microscopy demonstrated that rpiA and rpe mutants were able to resume late intracellular multiplication. To better understand the links between PPP and other metabolic networks in the bacterium, we also performed an extensive proteo-metabolomic analysis of these mutants. We show that the PPP constitutes a major bacterial metabolic hub with multiple connections to glycolysis, the tricarboxylic acid cycle and other pathways, such as fatty acid degradation and sulfur metabolism. Altogether our study highlights how PPP plays a key role in the pathogenesis and growth of Francisella in its intracellular niche.

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Section: Plos Pathogensmentioning

confidence: 99%

The pentose phosphate pathway constitutes a major metabolic hub in pathogenic Francisella

et al. 2021

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“…Extracellular Ggt supports a model whereby GisABCD imports Ggt cleavage products, whereas intracellular Ggt suggests GisABCD imports GSH and GSSG intact 18,19 . We used the previously described His-tagged Ggt expression vector (Ggt-His) that functionally complements the ggt::Tn mutant (Supplementary Fig.…”

Section: Ggt Hydrolyzes Gsh and Gssg γ-Bonds And Is Cell Associated A Hallmark Of γ-Glutamylmentioning

confidence: 68%

“…GSH concentrations range between 0.5 and 10 mM in mammalian tissues, making it a relatively abundant source of nutrient sulfur for invading pathogens [9][10][11][12][13][14][15][16][17][18][19][20] . In addition to Cys, GSH consists of glutamate and glycine.…”

mentioning

confidence: 99%

The glutathione import system satisfies the Staphylococcus aureus nutrient sulfur requirement and promotes interspecies competition

Lensmire¹,

Wischer²,

Sosinski

et al. 2021

Preprint

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Sulfur is an indispensable element for proliferation of bacterial pathogens. Prior studies indicated that the human pathogen, Staphylococcus aureus utilizes glutathione (GSH) as a source of nutrient sulfur; however, mechanisms of GSH acquisition are not defined. Here, we identify a previously uncharacterized five-gene locus comprising a putative ABC-transporter and γ–glutamyl transpeptidase (ggt) that promotes S. aureus proliferation in medium supplemented with either reduced or oxidized GSH (GSSG) as the sole source of nutrient sulfur. Based on these phenotypes, we name this transporter the Glutathione import system (GisABCD). We confirm that Ggt is capable of cleaving GSH and GSSG γ–bonds and that this process is required for their use as nutrient sulfur sources. Additionally, we find that the enzyme is cell associated. Bioinformatic analyses reveal that only Staphylococcus species closely related to S. aureus encode GisABCD-Ggt homologues. Homologues are not detected in Staphylococcus epidermidis. Consequently, we establish that GisABCD-Ggt provides a competitive advantage for S. aureus over S. epidermidis in a GSH-dependent manner. Overall, this study describes the discovery of a nutrient sulfur acquisition system in S. aureus that targets GSH and promotes competition against other staphylococci commonly associated with the human microbiota.

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“…Reads with 16 bp were mapped to the Lm genome using bowtie2 ( 54 ). The scripts were used to identify reads corresponding to insertions in TA sites and tally only those insertions with reads mapping from both ends of the transposon ( 55 ). Genes were screened according to fold change and BH value (|FC|≥2, BH ≤ 0.01).…”

Section: Methodsmentioning

confidence: 99%

Functional Genomics Identified Novel Genes Involved in Growth at Low Temperatures in Listeria monocytogenes

Pang

Liu

et al. 2022

Microbiol Spectr

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Tn-Seq reveals hidden complexity in the utilization of host-derived glutathione in Francisella tularensis

Cited by 20 publications

References 73 publications

The pentose phosphate pathway constitutes a major metabolic hub in pathogenic Francisella

The pentose phosphate pathway constitutes a major metabolic hub in pathogenic Francisella

The glutathione import system satisfies the Staphylococcus aureus nutrient sulfur requirement and promotes interspecies competition

Functional Genomics Identified Novel Genes Involved in Growth at Low Temperatures in Listeria monocytogenes

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