Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Group B Streptococcus genes controlled by the CiaR response regulator

ABSTRACT: The purpose of this study was to identify Group B Streptococcus (GBS) genes that are controlled by the CiaR response regulator. Deletion of the GBS ciaR gene resulted in a significant decrease in intracellular survival within neutrophils, murine macrophages, and human BMEC, which was linked to increased susceptibility to killing by antimicrobial peptides, lysozyme, and reactive oxygen species. Furthermore, competition experiments in mice showed that wild-type GBS had a significant survival advantage compared to the isogenic ciaR mutant. Microarray analysis comparing gene expression between the wild-type and ciaR mutant strains revealed several CiaR-regulated genes that may contribute to GBS stress tolerance and subversion of host defenses. Two cultures each of the wild-type GBS strain (COH1) and the isogenic ciaR mutant were grown in Todd-Hewitt broth to an optical density of 0.3. Cells were disrupted by shaking with glass beads and RNA was isolated by a Trizol method. A custom Affymetrix chip with a design based on the COH1 genomic sequence was used to analyze gene expression.

ORGANISM(S): Streptococcus agalactiae

SUBMITTER: Daniel Shelver

PROVIDER: E-GEOD-14259 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The CiaR response regulator in group B Streptococcus promotes intracellular survival and resistance to innate immune defenses.

Quach Darin D van Sorge Nina M NM Kristian Sascha A SA Bryan Joshua D JD Shelver Daniel W DW Doran Kelly S KS

Journal of bacteriology 20081229 7

Group B Streptococcus (GBS) is major cause of invasive disease in newborn infants and the leading cause of neonatal meningitis. To gain access to the central nervous system (CNS), GBS must not only subvert host defenses in the bloodstream but also invade and survive within brain microvascular endothelial cells (BMEC), the principal cell layer composing the blood-brain barrier (BBB). While several GBS determinants that contribute to the invasion of BMEC have been identified, little is known about ...[more]

PMID: 19114476

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Project description:The protein secretory pathway must maintain homoeostasis while producing a wide assortment of proteins in different conditions. It is also used extensively to produce many useful proteins in biotechnology. As such, secretory pathway dysfunction can be highly detrimental to the cell, resulting in the molecular basis for many human diseases, and can drastically inhibit product titers in biochemical production. Because the secretory pathway is a highly-integrated, multi-organelle system, dysfunction can happen at many levels and dissecting the root cause can be challenging. To better understand some of these dysfunctions, we measured multiple systems-level states of the cell (physiology, transcriptome, metabolism) while secreting a small protein (insulin precursor) or a large protein (?-amylase). This was carried out in the presence and absence of HAC1, a key transcription factor in maintaining secretory homeostasis. Clear trends in cellular stress were apparent across multiple data resulting from our perturbations. In particular, processes involving (1) degradation of protein / recycling amino acids, (2) overall transcription/translation repression, and (3) oxidative stress. Apparent runaway oxidative radical production was explained by a thermodynamic model that we put forward for disulfide formation in the endoplasmic reticulum. This model predicts that balancing the relative rates of protein folding and disulfide bond formation are key to easing oxidative stress. These predictions have direct implications in how to engineer a broad range of recombinant proteins for secretion and provide potential hypotheses for the root causes of several secretory-associated diseases. Yeast strains were constructed that produce and secrete (a) IP or (b) ?-amylase and were compared to yeast strains containing (c) an empty vector in both wild-type and HAC1 deletion backgrounds. These strains are named WN (WT with empty vector), WI (WT secreting IP), WA (WT secreting ?-amylase), dN (?hac1 with empty vector), dI (?hac1 secreting IP), and dA (?hac1 secreting ?-amylase). Strains were characterized in batch fermentation and samples were taken in mid-exponential phase. Triplicate fermentations were carried out for each strain.

Project description:Objectives: Development of daptomycin resistance (DAPR) in Staphylococcus aureus is associated with clinical treatment failures. Mechanism(s) of such resistance has not been clearly defined. Methods: We studied an isogenic daptomycin-susceptible (DAPS) and daptomycin-resistant (DAPR) S. aureus strain pair (616; 701) from a patient with relapsing endocarditis during daptomycin treatment, using comparative transcriptomic and proteomic techniques. Results. Minor differences in genome content were found between strains by DNA hybridization. Transcriptomic analyses identified a number of genes differentially expressed in important functional categories: cell division, metabolism of bacterial envelopes and global regulation. Of note, the DAPR isolate exhibited reduced expression of the major cell wall autolysis gene coincident with upregulation of genes involved in wall teichoic acid production. Using quantitative (q)RT-PCR on gene cadre putatively involved in cationic peptide resistance, we formulated a putative regulatory network compatible with microarray data-sets, mainly implicating bacterial envelopes. Of interest, qRT-PCR of this same gene cadre from two distinct isogenic DAPS/DAPR clinical strain pairs revealed evidence of other strain dependent networks operative in the DAPR phenotype. Comparative proteomics of 616 vs 701 revealed differential abundance of proteins in various functional categories including: cell-wall associated targets and biofilm-formation proteins. Phenotypically, strains 616 and 701 showed major differences in ability to develop bacterial biofilms in presence of the antibacterial lipid, oleic acid. Conclusions: Compatible with previous in vitro observations, in vivo acquired DAPR in S. aureus is a complex, multistep phenomenon allowing for: i) strain dependent phenotypes; ii) transcriptome adaptation; and iii) modification of lipid and protein content of cellular envelopes. Daptomycin suceptible strain vs daptomycin non suceptible strain after daptomycin treatment

Dataset Information

Group B Streptococcus genes controlled by the CiaR response regulator

Publications

The CiaR response regulator in group B Streptococcus promotes intracellular survival and resistance to innate immune defenses.

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