Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence

ABSTRACT: Staphylococcus aureus is a significant cause of human infection. Here, we demonstrate that mutations in the transcriptional repressor of purine biosynthesis, purR, enhance the pathogenic potential of S. aureus. Indeed, systemic infection with purR mutants causes accelerated mortality in mice, which is due to aberrant up-regulation of fibronectin binding proteins (FnBPs). Remarkably, purR mutations can arise upon exposure of S. aureus to stress, such as an intact immune system. In humans, naturally occurring anti-FnBP antibodies exist that, while not protective against recurrent S. aureus infection, ostensibly protect against hypervirulent S. aureus infections. Vaccination studies support this notion, where anti-Fnb antibodies in mice protect against purR hypervirulence. These findings provide a novel link between purine metabolism and virulence in S. aureus.

ORGANISM(S): Staphylococcus aureus

PROVIDER: GSE124869 | GEO | 2019/02/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Identification and application of a panel of constitutive promoters for gene overexpression in Staphylococcus aureus

Project description:Staphylococcus aureus is a leading pathogen that is currently the most common cause of infection in hospitalized patients. An in-depth genetic analysis of S. aureus virulence genes contributing to pathogenesis is needed to develop novel antimicrobial therapies. However, tools for genetic manipulation in S. aureus are limited, particularly those for gene expression. Here, 38 highly expressed genes were identified in S. aureus USA300_FPR3757 via RNA-seq. Promoter regions from 30 of these genes were successfully cloned, of which 20 promoters exhibited a wide range of activity. By utilizing these active promoters, 20 S. aureus-E. coli shuttle vectors were constructed and evaluated by expressing an egfp reporter gene. Expression of egfp gene under the control of different promoters was confirmed and quantified by Western-blot and qPCR, which suggested that the activity of these promoters varied from 18% to 650% of the activity of PsarA, a widely used promoter for gene expression currently. In addition, our constructed vectors were verified to be of high compatibility on gene expression in different S. aureus strains. Furthermore, these vectors were evaluated and used in overexpressing two endogenous proteins in S. aureus, namely, catalase and the transcriptional repressor of purine biosynthesis (purR). Meanwhile, the physiological functions and phenotypes of overexpressed purR and catalase in S. aureus were validated. Altogether, this evidence indicates that our constructed vectors provide a wide range of promoter activity on gene expression in S. aureus. This developed system will provide a powerful tool for the direct analysis of target gene function in staphylococcal cells.

2021-11-30 | GSE189644 | GEO

The nucleotide messenger (p)ppGpp is an anti-inducer of the purine synthesis transcription regulator PurR in Bacillus

Project description:The nucleotide messenger (p)ppGpp allows bacteria to adapt to fluctuating environments by reprogramming the transcriptome. Despite its well-recognized role in gene regulation, (p)ppGpp is only known to directly affect transcription in Proteobacteria by binding to the RNA polymerase. Here we reveal a different mechanism of gene regulation by (p)ppGpp in Firmicutes from soil bacteria to pathogens: (p)ppGpp directly binds to the transcription factor PurR to downregulate purine biosynthesis. We identified PurR as a receptor of (p)ppGpp in Bacillus anthracis and revealed that (p)ppGpp strongly enhances PurR binding to its regulon in the Bacillus subtilis genome. A co-structure reveals that (p)ppGpp binds to a PurR pocket reminiscent of the active site of PRT enzymes that has been repurposed to serve a purely regulatory role, where the effectors (p)ppGpp and PRPP compete to allosterically control transcription. PRPP inhibits PurR DNA binding to induce transcription of purine synthesis genes, whereas (p)ppGpp antagonizes PRPP to enhance PurR DNA binding and repress transcription. A (p)ppGpp-refractory purR mutant fails to downregulate purine synthesis genes upon starvation. Our work establishes the precedent of (p)ppGpp as a classical effector of transcription repressors and reveals the key function of (p)ppGpp in regulating nucleotide synthesis through gene regulation, from the human intestinal tract to host-pathogen interfaces.

2021-12-10 | GSE185164 | GEO

Non-protective immune imprint underlies failure of S. aureus IsdB vaccine

Project description:The failure to date of all S. aureus vaccine trials has been a conundrum and underlines fundamental flaws in current translational models. A major difference between humans and laboratory animals is the early and frequent exposure of humans to S. aureus compared to animals, which is not accounted for in vaccine studies. In recapitulating the failed IsdB human vaccine trial, we showed that mice previously infected with S. aureus do not mount a protective vaccine antibody response, unlike naïve mice. S. aureus infection induces robust but non-neutralizing anti-IsdB antibodies that target different but overlapping IsdB epitopes compared to IsdB vaccine. In the setting of prior S. aureus infection, however, IsdB vaccine recalls the non-protective humoral response which further competes and reduces efficacy of protective vaccine-generated specific antibodies. Vaccination against the heme-binding domain of IsdB or select IsdB epitope can overcome interference by S. aureus infection. Using an adoptive transfer model, we showed that human serum antibodies against IsdB and another vaccine target, ClfA, are also non-protective and blocked anti-staphylococcal immunity conferred by passive immunizations. Overall, our study demonstrates proof of concept that failure of anti-S. aureus active and passive immunizations could be explained by non-protective imprint of prior host-pathogen interaction.

2023-01-28 | GSE193543 | GEO

Staphylococcus aureus mutants resistant to the feed-additive monensin show increased virulence and altered purine metabolism

Project description:Ionophores are antibacterial compounds that affect bacterial growth by changing intracellular concentrations of the essential cations, sodium and potassium. They are extensively used in animal husbandry to increase productivity and reduce infectious diseases. Given their widespread usage, it is important to determine the potential negative consequences of ionophore use on human and animal health. In this study, we demonstrate that exposure to the ionophore monensin can select for resistant mutants in the human and animal pathogen Staphylococcus aureus, with a majority of the resistant mutants showing increased growth rates in vitro and/or in mice. Whole-genome sequencing and proteomics analysis of the resistant mutants show that the resistance phenotype is associated with de-repression of de novo purine synthesis, which could be achieved through mutations in different transcriptional regulators including mutations in the gene purR, the repressor of the purine de novo synthesis pathway. This study shows that mutants with reduced susceptibility to the ionophore monensin can be readily selected and highlights an unexplored link between ionophore resistance, purine metabolism and fitness in pathogenic bacteria.

2024-01-09 | PXD047199 | Pride

RNA-Seq of WT Staphylococcus aureus and dpurR grown to exponential and stationary phase

Project description:We report here that mutants for purR display altered transcriptional profiles compared to WT S. aureus at multiple stages of growth.

2019-06-12 | GSE132179 | GEO

Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence

Project description:Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence

| PRJNA514046 | ENA

Transcriptome comparison of M1T1 WT, AP and delta CovS strains

Project description:Group A streptococci (GAS) may engage different sets of virulence strategies, depending on the site of infection and host context. We previously isolated 2 phenotypic variants of a globally disseminated M1T1 GAS clone: a virulent wild-type (WT) strain, characterized by a SpeB(+)/SpeA(-)/Sda1(low) phenotype, and a hypervirulent animal-passaged (AP) strain, better adapted to survive in vivo, with a SpeB(-)/SpeA(+)/Sda1(high) phenotype. This AP strain arises in vivo due to the selection of bacteria with mutations in covS, the sensor part of a key 2-component regulatory system, CovR/S. To determine whether covS mutations explain the hypervirulence of the AP strain, we deleted covS from WT bacteria (DeltaCovS) and were able to simulate the hypervirulence and gene expression phenotype of naturally selected AP bacteria. Correction of the covS mutation in AP bacteria reverted them back to the WT phenotype. Our data confirm that covS plays a direct role in regulating GAS virulence.

2010-09-22 | GSE24246 | GEO

Transcriptome comparison of M1T1 WT, AP and delta CovS strains

2010-09-22 | E-GEOD-24246 | biostudies-arrayexpress

Towards in vivo regulatory kinetics: PurR activation by PRPP during purine depletion in Lactococcus

Project description:Short-term adaptation to changing environments relies on regulatory elements translating changing metabolite concentrations into a specifically optimized transcriptome. So far the focus of analyses has been divided between regulatory elements identified in vivo and kinetic studies of small molecules interacting with the regulatory elements in vitro. Here we describe how in vivo Regulatory Kinetics can describe a regulon through the effects of the metabolite controlling it, exemplified by temporal purine exhaustion in Lactococcus lactis. We deduced a causal relation between the pathway precursor 5-phosphoribosyl-1-pyrophosphate (PRPP) and each individual mRNA levels, whereby unambiguous and homogenous relations could be obtained for PurR regulated genes, thus linking a specific regulon to a specific metabolite. As PurR activates gene expression upon binding of PRPP, the pur mRNA curves reflect the in vivo kinetics of PurR PRPP binding and activation. The method singled out the xpt-pbuX operon as kinetically distinct, which was found to be caused by a guanine riboswitch whose regulation was overlaying the PurR regulation. The strategy outlined here can be adapted to analyze the individual effects of members from larger metabolomes in virtually any organism, for elucidating regulatory networks in vivo. Agilent 8x15k custom microarrays Fifteen samples from two cultures were taken in a time-course experiment.

2013-12-01 | E-GEOD-52135 | biostudies-arrayexpress

T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infections

Project description:CD4+ T cells are key components of the immune response during lung infections and can mediate protection against tuberculosis (TB) or influenza. However, CD4+ T cells can also promote lung pathology during these infections, making it unclear how these cells control such discrepant effects. Using mouse models of hypervirulent TB and influenza, we observed that exaggerated accumulation of parenchymal CD4+ T cells promotes lung damage. Low numbers of lung CD4+ T cells, in contrast, are sufficient to protect against hypervirulent TB. In both situations, lung CD4+ T cell accumulation is mediated by CD4+ T cell-specific expression of the extracellular ATP (eATP) receptor P2RX7. P2RX7 upregulation in lung CD4+ T cells promotes expression of the chemokine receptor CXCR3 and favors in situ proliferation. Our findings suggest that direct sensing of lung eATP by CD4+ T cells is critical to induce tissue CD4+ T cell accumulation and pathology during lung infections.

2024-02-14 | GSE244194 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data