Redox, amino acid, and fatty acid metabolism intersect with bacterial virulence in the gut

Pifer, Reed; Russell, Regan M.; Kumar, Aman; Curtis, Meredith M.; Sperandio, Vanessa

doi:10.1073/pnas.1813451115

Cited by 40 publications

(45 citation statements)

References 32 publications

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“…In contrast, the PmrA/B response of C. burnetii is not linked to metabolic changes but to transition to a virulent phenotype. Transcriptional virulence induction in response to amino acids also appears true for enterohemorrhagic Escherichia coli (EHEC) as a recent report indicated that exogenous cysteine can be sensed by the EHEC cysteine utilization regulator CutR, leading to increased expression of genes within the virulence-associated locus of the enterocyte effacement pathogenicity island (61).…”

Section: Discussionmentioning

confidence: 99%

Lysosomal degradation products induce Coxiella burnetii virulence

Newton

Thomas

Reed

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Coxiella burnetiiis an intracellular pathogen that replicates in a lysosome-like vacuole through activation of a Dot/Icm-type IVB secretion system and subsequent translocation of effectors that remodel the host cell. Here a genome-wide small interfering RNA screen and reporter assay were used to identify host proteins required for Dot/Icm effector translocation. Significant, and independently validated, hits demonstrated the importance of multiple protein families required for endocytic trafficking of theC. burnetii-containing vacuole to the lysosome. Further analysis demonstrated that the degradative activity of the lysosome created by proteases, such as TPP1, which are transported to the lysosome by receptors, such as M6PR and LRP1, are critical forC. burnetiivirulence. Indeed, theC. burnetiiPmrA/B regulon, responsible for transcriptional up-regulation of genes encoding the Dot/Icm apparatus and a subset of effectors, induced expression of a virulence-associated transcriptome in response to degradative products of the lysosome. Luciferase reporter strains, and subsequent RNA-sequencing analysis, demonstrated that particular amino acids activate theC. burnetiiPmrA/B two-component system. This study has further enhanced our understanding ofC. burnetiipathogenesis, the host–pathogen interactions that contribute to bacterial virulence, and the different environmental triggers pathogens can sense to facilitate virulence.

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Section: Discussionmentioning

confidence: 99%

Lysosomal degradation products induce Coxiella burnetii virulence

Newton

Thomas

Reed

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Examples of metabolic regulators that display dual-functional roles as they pertain to controlling virulence have been previously reported in a number of pathogens. It was recently shown that Citrobacter rodentium, the surrogate in vivo model organism for enterohemorrhagic Escherichia coli, uses an intricate circuit of amino and fatty acid regulators to control the expression of virulence genes in the infected gut (37). Additionally, the intracellular pathogen Listeria monocytogenes uses the branched-chain amino acid sensor CodY to directly control the activity of the master virulence regulator prfA (38).…”

Section: Discussionmentioning

confidence: 99%

The purine biosynthesis regulator PurR moonlights as a virulence regulator in Staphylococcus aureus

Sause

Balasubramanian

Irnov

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The pathogen Staphylococcus aureus colonizes and infects a variety of different sites within the human body. To adapt to these different environments, S. aureus relies on a complex and finely tuned regulatory network. While some of these networks have been well-elucidated, the functions of more than 50% of the transcriptional regulators in S. aureus remain unexplored. Here, we assess the contribution of the LacI family of metabolic regulators to staphylococcal virulence. We found that inactivating the purine biosynthesis regulator purR resulted in a strain that was acutely virulent in bloodstream infection models in mice and in ex vivo models using primary human neutrophils. Remarkably, these enhanced pathogenic traits are independent of purine biosynthesis, as the purR mutant was still highly virulent in the presence of mutations that disrupt PurR’s canonical role. Through the use of transcriptomics coupled with proteomics, we revealed that a number of virulence factors are differentially regulated in the absence of purR. Indeed, we demonstrate that PurR directly binds to the promoters of genes encoding virulence factors and to master regulators of virulence. These results guided us into further ex vivo and in vivo studies, where we discovered that S. aureus toxins drive the death of human phagocytes and mice, whereas the surface adhesin FnbA contributes to the increased bacterial burden observed in the purR mutant. Thus, S. aureus repurposes a metabolic regulator to directly control the expression of virulence factors, and by doing so, tempers its pathogenesis.

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“…using the Ashwell pathway, which is under the control of the ExuR transcriptional regulator 9,10 . A high throughput screen for metabolic pathways and transcriptional factors that regulate LEE gene expression identified ExuR as a LEE regulator 13 . ExuR is a member of the GntR family of transcriptional regulators 14 , has been previously characterized as a regulator of sugar acid catabolism in E. coli 15,16 , and is responsive to galacturonic-acid [17][18][19] .…”

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confidence: 99%

Diet-derived galacturonic acid regulates virulence and intestinal colonization in enterohaemorrhagic Escherichia coli and Citrobacter rodentium

et al. 2019

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Enteric pathogens sense the complex chemistry within the gastrointestinal (GI) tract to efficiently compete with the resident microbiota and establish a colonization niche. Here we show that enterohemorrhagic E. coli (EHEC), and its surrogate murine infection model Citrobacter rodentium, sense galacturonic-acid to initiate a multi-layered program towards successful mammalian infection. Galacturonic-acid utilization as a carbon source aids the initial pathogen expansion. The main source of galacturonic-acid is dietary pectin, which is broken into galacturonic-acid by the prominent member of the microbiota, Bacteroides thetaiotamicron (Bt). This regulation occurs through the ExuR transcription factor. However, galacturonic-acid is also sensed as a signal through ExuR to modulate the expression of the genes encoding a molecular syringe known as a type three secretion system (T3SS) leading to infectious colitis and inflammation. Galacturonic-acid moonlights as a nutrient and a signal directing the exquisite microbiota-pathogen relationships within the GI tract. Importantly, this work highlights that differential dietary sugar availability impacts the relationship between the microbiota and enteric pathogens, as well as disease outcomes. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Redox, amino acid, and fatty acid metabolism intersect with bacterial virulence in the gut

Cited by 40 publications

References 32 publications

Lysosomal degradation products induce Coxiella burnetii virulence

Lysosomal degradation products induce Coxiella burnetii virulence

The purine biosynthesis regulator PurR moonlights as a virulence regulator in Staphylococcus aureus

Diet-derived galacturonic acid regulates virulence and intestinal colonization in enterohaemorrhagic Escherichia coli and Citrobacter rodentium

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