Transketolase of Staphylococcus aureus in the Control of Master Regulators of Stress Response During Infection

Tan, Xin; Ramond, Elodie; Jamet, Anne; Barnier, Jean-Philippe; Decaux-Tramoni, Baptiste; Dupuis, Marion; Euphrasie, Daniel; Tros, Fabiola; Nemazanyy, Ivan; Ziveri, Jason; Nassif, Xavier; Charbit, Alain; Coureuil, Mathieu

doi:10.1093/infdis/jiz404

Cited by 17 publications

(23 citation statements)

References 48 publications

(43 reference statements)

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“…On the contrary, tktA inactivation was accompanied by decreased concentrations of the PPP intermediate sedoheptulose-7P (S-7P) as well as of the glycolytic end product pyruvate. Of note, our lab recently showed that in the Gram-positive pathogen Staphylococcus aureus , inactivation of tktA also led to deregulation of whole-cell metabolism [ 25 ] and, as in Francisella , to accumulation of R-5P and decreased amounts of S-7P.…”

Section: Resultsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

“…In the Gram-positive pathogen Staphylococcus aureus , our laboratory has recently shown that tktA inactivation also led to dysregulation of the whole cell metabolism [ 25 ]. As in Francisella , an accumulation of R-5P and a decrease in S-7P amount were recorded in the Δ tktA mutant compared to wild-type S .…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…However, transketolase is also a key enzyme of the oxidative branch of the pentose phosphate pathway, which contributes to bacterial tolerance (persistence) to oxidative stress by producing the cellular NADPH required for intracellular reactive oxygen species detoxification ( 70 ). In St. aureus , the inactivation of the transketolase-encoding tkt gene affected bacterial pathogenesis, particularly the intracellular proliferation and tissue-colonizing ability ( 71 ). Whether upregulation of transketolases in hemolymph-responsive bacteria is related to the production of ansamycins or to link central metabolism to redox homeostasis needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Tandem Mass Tag-Based Quantitative Proteomics and Virulence Phenotype of Hemolymph-Treated Bacillus thuringiensis kurstaki Cells Reveal New Insights on Bacterial Pathogenesis in Insects

et al. 2021

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After ingestion by a susceptible insect and damaging its midgut epithelium, the bacterium Bacillus thuringiensis (Bt) reaches the insect blood (hemolymph), where it propagates despite the host’s antimicrobial defenses and induces insect death by acute septicemia. Although the hemolymph stage of the Bt toxic pathway is determinant for the infested insects’ fate, the response of Bt to hemolymph and the latter’s role in bacterial pathogenesis has been poorly explored.

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“…Microbial TKT has been also implicated in the metabolism of exopolysaccharides, high-molecular-weight polymers secreted by microbes into the microbial ecosystem, promoting a shift in the microbial metabolism to adapt to new dietary conditions and render more reducing power [42]. TKT expression confers microbes an important adaptation in sourcing energy, including saccharides produced by other microbes such as bifidobacteria, and thus allows rapid host colonisation [43].…”

Section: Discussionmentioning

confidence: 99%

Peripheral tolerance to insulin is encoded by mimicry in the microbiome

Garćıa

Paterou

Lee

et al. 2019

Preprint

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How organisms achieve sustained peripheral tolerance throughout their lifetime, a correct immune discrimination between self and non-self, remains poorly understood. Host-microbiome interactions carry fundamental information that facilitates this process. We hypothesize that commensal microbes are under evolutionary pressure to develop epitopes that, when presented along with other antigens from their own bacterial community, lead to an overall tolerogenic self classification by the host immune system. Hosts, which have co-evolved with commensals, may rely on mimotopes, bacterial epitopes that are indistinguishable from key self epitopes, as a homeostatic feedback mechanism to establish and maintain tolerance. Using a probabilistic sequence model of peptide mimicry, we show that the gut microbiome contains a set of genes that are likely to trigger identical immune responses to insulin B 9-25, a widely distributed self epitope across tissues and the primary autoantigen in type 1 diabetes. Similarities in the antigen receptor sequences determined from CD4 T cells reacting to insulin epitopes and mimotopes provide experimental evidence for mimicry. All predicted high posterior probability mimotopes belong to the transketolase superfamily, an enzyme that allows efficient harvest of commensal-derived sugar polymers and dietary fibre, an advantage during host colonisation. Microbial transketolase upregulation during infant weaning coincides in time with the peak in autoantibody development against insulin. Abundance changes in bacterial genera that carry these mimotopes have also been observed to precede disease diagnosis. Our findings suggest gut dysbiosis followed by immune response to insulin mimotopes as a primary cause of type 1 diabetes, and may contribute towards unraveling similar causal patterns in a wide variety of disorders.

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Transketolase of Staphylococcus aureus in the Control of Master Regulators of Stress Response During Infection

Cited by 17 publications

References 48 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

Tandem Mass Tag-Based Quantitative Proteomics and Virulence Phenotype of Hemolymph-Treated Bacillus thuringiensis kurstaki Cells Reveal New Insights on Bacterial Pathogenesis in Insects

Peripheral tolerance to insulin is encoded by mimicry in the microbiome

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