Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Structural basis of virulence activation in Francisella tularensis

ABSTRACT: The bacterium, Francisella tularensis (Ft), is one of the most infectious agents known and classified as a category A bioweapon. Ft virulence is controlled by a unique set of transcription regulators, the MglA-SspA heterodimer, PigR, and the stress signal, ppGpp. These factors activate Francisella pathogenicity island (FPI) gene expression, which is required for virulence. MglA-SspA is expressed during infection and constitutively associates with the σ70 associated RNAP holoenzyme (RNAPσ70), indicating that RNAPσ70-(MglA-SspA) is a virulence specific polymerase. How virulence activation is mediated by these components, however, is unknown. Here we report cryo-EM structures of FtRNAPσ70, FtRNAPσ70-(MglA-SspA) and RNAPσ70-(MglA-SspA)-ppGpp-PigR complexes with promoter DNA. FtRNAPσ70-DNA and FtRNAPσ70-(MglA-SspA)-DNA structures and RT-PCR analyses show MglA-SspA stabilizes σ70 binding to DNA to regulate FPI-independent, virulence-enhancing genes. Strikingly, an Escherichia coli RNAPσ70 complex with EcSspA suggests this is a general mechanism for SspA-like regulation of bacterial RNAPσ70. Finally, our FtRNAP-σ70-(MglA-SspA)-ppGpp-PigR-DNA structure reveals that ppGpp binds to MglA-SspA to tether the DNA-binding activator, PigR, to FPI promoters. PigR in turn recruits FtRNAP CTDs to two DNA upstream (UP) elements, generating stable FPI transcription complexes. Thus, these studies unveil a novel paradigm for pathogenesis in Ft involving a virulence-specific RNAP that employs two (MglA-SspA)-based strategies to activate virulence genes.

ORGANISM(S): Francisella tularensis

PROVIDER: GSE150932 | GEO | 2020/11/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

CedA: A General Transcription Factor from E. coli with a Distinct Mechanism of Action

Project description:Gene expression in E. coli is controlled by well-established mechanisms that activate or repress transcription. Here, we identify CedA as an unconventional transcription factor specifically associated with the RNA polymerase (RNAP) σ70 holoenzyme. Structural and biochemical analysis of CedA bound to RNAP reveal that it bridges distant domains of β and σ70 subunits to stabilize an open-promoter complex. Remarkably, CedA does so without contacting DNA. We further show that cedA is strongly induced in response to amino acid starvation, oxidative stress, and aminoglycosides. CedA provides a basal level of tolerance to these clinically relevant antibiotics, as well as to rifampicin and peroxide. Finally, we show that CedA modulates transcription of hundreds of bacterial genes, which explains its pleotropic effect on cell physiology and pathogenesis.

2023-09-17 | PXD039446 | Pride

Proteins of anti-sigma70 and anti-RNAP immunoprecipitates in bacteria

Project description:As part of the project aimed at the interaction of RNA with RNA polymerase and primary sigma factor in bacteria we analyzed anti-σ70 antibody immunoprecipitates from Mycobacterium smegmatis stationary phase to identify proteins in σA complex in non-treated cells. We performed mass spectrometry analysis of anti-σ70 antibody and anti-RNAP immunoprecipitates from Corynebacterium glutamicum stationary phase to identify proteins present in σA and RNAP complexes.

2024-03-06 | PXD047705 | Pride

(p)ppGpp promotes Enterococcus faecalis virulence in a murine model of catheter-associated urinary tract infection

Project description:In Firmicutes, the nutrient-sensing regulators (p)ppGpp, the effector molecule of the stringent response, and CodY work in tandem to maintain bacterial fitness during infection. Here, we tested (p)ppGpp and codY mutant strains of Enterococcus faecalis in a catheter-associated urinary tract infections (CAUTI) mouse model and used global transcriptional analysis to investigate the (p)ppGpp and CodY relationship. Absence of (p)ppGpp or single inactivation of codY led to lower bacterial loads in catheterized bladders, and diminished biofilm formation on fibrinogen-coated surfaces under in vitro and in vivo conditions. Single inactivation of the bifunctional (p)ppGpp synthetase/hydrolase rel did not affect virulence supporting previous evidence that association of (p)ppGpp with enterococcal virulence is not dependent on activation of the stringent response. Inactivation of codY in the (p)ppGpp0 strain restored E. faecalis virulence in the CAUTI model as well as the ability to form biofilms in vitro. Transcriptome analysis revealed that inactivation of codY restores, for the most part, the dysregulated metabolism of (p)ppGpp0 cells. While a clear linkage between (p)ppGpp and CodY with expression of virulence factors could not be established, targeted transcriptional analysis indicate that a possible association between (p)ppGpp and c-di-AMP signaling pathways in response to the conditions found in the bladder may plays a role in enterococcal CAUTI. Collectively, this study identifies the (p)ppGpp-CodY network as an important contributor to enterococcal virulence in catheterized mouse bladder and supports that basal (p)ppGpp pools promote virulence through maintenance of a balanced metabolism during adverse conditions.

2019-05-25 | GSE131749 | GEO

Transcriptomes of ΔrelAspoT and ΔdksA mutants of Haemophilus ducreyi in mid-log, transition, and stationary phase

Project description:To better understand the role of the (p)ppGpp-mediated stringent response in control of H. ducreyi virulence determinants, here we defined genes potentially regulated by either (p)ppGpp or DksA by using RNA-seq. We were able to show that loss of either (p)ppGpp or DksA resulted in dysregulation of multiple genes including several known virulence determinants. We also show that loss of (p)ppGpp or DksA resulted in differential expression of putative H. ducreyi small RNAs.

2015-06-04 | GSE67202 | GEO

Effect of ppGpp on Salmonella Typhimurium gene expression

Project description:The expression profile of an S. Typhimurium mutant strain unable to synthesise ppGpp (relAspoT deletions) was compared to the wild-type strain. The effect of ppGpp on virulence gene expression was studied under 4 different growth conditions that induce virulence gene expression. Keywords: genetic modification Study comprised 4 separate experiments (with 2 strains and 4 replicates for each strain per growth condition). The experiments were indirect comparisons using Salmonella genomic DNA as the comparator which also acted as the control for spot quality.

2010-06-11 | E-GEOD-4631 | biostudies-arrayexpress

Effect of ppGpp on Salmonella Typhimurium gene expression

2006-05-30 | GSE4631 | GEO

Comparative RNA-seq analysis of the transcriptome of the Pseudomonas aeruginosa PAO1 wild-type strain with that of the ΔvreR mutant

Project description:Bacterial gene expression is controlled by modifying the promoter affinity of the RNA polymerase (RNAP). This control occurs through the substitution of the RNAP σ subunit and by the interaction with transcription factors. The pathogen Pseudomonas aeruginosa contains several σ factors, including σVreI. This protein belongs to the extracytoplasmic function group of the σ70 family. Expression and activity of σECFs are tightly regulated and only occur in response to specific signals. σVreI is encoded within the vreAIR gene cluster. The expression of this cluster occurs in response to inorganic phosphate (Pi) limitation. σVreI activity is modulated by VreR anti-sigma factor, which keeps σVreI inactive. In response to a still unidentified host signal, VreR is proteolytically degraded and σVreI released and activated. σVreI interacts then with the RNAP and targets expression of the σVreI regulon, which includes virulence genes that increase P. aeruginosa pathogenicity. In this work, we compared the transcriptome of the P. aeruginosa PAO1 wild-type strain with that of the ΔvreR mutant upon bacterial growth in Pi starvation. Forty-six transcripts were more abundant in the ΔvreR mutant than in the PAO1 wild-type strain, and nine were less abundant, including the vreR transcript.

2019-03-13 | GSE122253 | GEO

Expression data from multiple strains of Francisella

Project description:Comparison of expression profiles of strains of Francisella to identify virulence factors We used custom microarrays to detail the global gene expression of four strains of Francisella (Schu4, LVS, OR960246, U112) and identified distinct classes of differentially expressed genes during this process.

2015-05-02 | GSE68478 | GEO

Expression data from mouse liver infected with Ft LVS (without or with LPS pretreatment)

Project description:Background: It has been shown previously that administration of Francisella tularensis (Ft) LVS lipopolysaccharide (LPS) protects mice against subsequent challenge with Ft LVS and blunts the pro-inflammatory cytokine response. Methods: To investigate further the molecular mechanisms that underlie Ft LVS LPS-mediated protection, we profiled global hepatic gene expression following Ft LVS LPS or saline pretreatment and subsequent Ft LVS challenge using Affymetrix arrays. Results: A large number of genes (> 3000) were differentially expressed at 48 hours post-infection. The degree of modulation of inflammatory genes by infection was clearly attenuated by LPS-pretreatment in the surviving mice. However, LPS alone had a subtle but significant effect on the gene expression profile of the uninfected mice. By employing gene set enrichment analysis, we discovered significant up-regulation of peroxisome proliferator activated receptors (PPARs) and their target genes in LPS-treated liver. Conclusions: We hypothesize that the LPS-induced blunting of pro-inflammatory response in mouse is, in part, mediated by PPARs (alpha and gamma).

2010-01-31 | GSE16207 | GEO

An AraC/XylS Family Transcriptional Regulator Modulates the Oxidative Stress Response of Francisella tularensis

Project description:Francisella tularensis is a Gram-negative bacterium that causes a fatal human disease known as tularemia. The Centers for Disease Control have classified F. tularensis as Category A Tier-1 Select Agent. The virulence mechanisms of Francisella are not entirely understood. Francisella possesses very few transcription regulators, and most of these regulate the expression of genes involved in intracellular survival and virulence. The F. tularensis genome sequence analysis reveals an AraC (FTL_0689) transcriptional regulator homologous to the AraC/XylS family of transcriptional regulators. In Gram-negative bacteria, AraC activates genes required for L-arabinose utilization and catabolism. The role of the FTL_0689 regulator in F. tularensis is not known. In this study, we characterized the role of FTL_0689 in gene regulation of F. tularensis and investigated its contribution to intracellular survival and virulence. The results demonstrate that FTL_0689 in Francisella is not required for L-arabinose utilization. Instead, FTL_0689 specifically regulates the expression of the oxidative and global stress response, virulence, metabolism, and other key pathways genes required by Francisella when exposed to oxidative stress. The FTL_0689 mutant is attenuated for intramacrophage growth, and mice infected with the FTL_0689 mutant survive better than wild-type F. tularensis LVS infected mice. Based on the deletion mutant phenotype, FTL_0689 was termed osrR (oxidative stress response regulator). Altogether, this study elucidates the role of the osrR transcriptional regulator in tularemia pathogenesis.

2021-10-13 | GSE183001 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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