The cop operon is required for copper homeostasis and contributes to virulence in Streptococcus pneumoniae
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PROVIDER: PRJNA143377 | ENA |
REPOSITORIES: ENA
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Project description:High levels of copper are toxic and therefore bacteria must limit free intracellular levels to prevent cellular damage. In this study, we show that a number of pneumococcal genes are differentially regulated by copper, including an operon encoding a CopY regulator, a protein of unknown function (CupA) and a P1-type ATPase, CopA, which is conserved in all sequenced Streptococcus pneumoniae strains. Transcriptional analysis demonstrated that the cop operon is induced by copper in vitro, repressed by the addition of zinc and is autoregulated by the copper-responsive CopY repressor protein. We also demonstrate that the CopA ATPase is a major pneumococcal copper resistance mechanism and provide the first evidence that the CupA protein plays a role in copper resistance. Our results also show that copper homeostasis is important for pneumococcal virulence as the expression of the cop operon is induced in the lungs and nasopharynx of intranasally infected mice, and a copA(-) mutant strain, which had decreased growth in high levels of copper in vitro, showed reduced virulence in a mouse model of pneumococcal pneumonia. Furthermore, using the copA(-) mutant we observed for the first time in any bacteria that copper homeostasis also appears to be required for survival in the nasopharynx. This SuperSeries is composed of the SubSeries listed below.
2011-07-10 | GSE30415 | GEO
Project description:Copper is both essential and toxic to living beings, which therefore tightly control its intracellular concentration. At the host-pathogen interface, copper is used by phagocytic cells to kill invading microorganisms. We investigated copper homeostasis in the whooping cough agent Bordetella pertussis, which lives in the human respiratory mucosa and has no environmental reservoir. B. pertussis has considerably streamlined copper homeostasis mechanisms relative to other Gram-negative bacteria. Its single remaining defense line against copper intoxication consists in a metallochaperone diverted for copper passivation and two enzymes involved in peroxide detoxification, which together fight two stresses encountered in phagolysosomes. The three proteins are encoded by an original, composite operon assembled in an environmental ancestor and which is under sensitive control by copper. Interestingly, this system appears to play a role in persistent infection in the nasal cavity of B. pertussis-infected mice. Combining responses to co-occurring stresses in a tailored operon reveals a new strategy adopted by a host-restricted pathogen to optimize survival at minimal energy expenditure.
2021-09-09 | PXD020900 | Pride
Project description:Purpose: CsoR, a copper responsive negative regulator of Mycobacterium tuberculosis has been shown to respond to copper and bind to its own regulon in in vitro experiments. Here we examine the role of CsoR in vivo by examining the impact of deletion of csoR on the host transcriptome. Methods: csoR was knocked out of M. tuberculosis H37Rv using the specialized transduction method developed by Bardarov et al (2002), followed by removal of the hygromycin marker with plasmid pYUB870. Both wild type and confirmed csoR knockout were grown in copper free Sauton's media to late log phase before harvesting for transcriptomic studies. RNA was extracted using a modified Trizol method prior to DNAse treatment and rRNA depletion. Sequencing was done on an Illumina HiSeq 2000, filtered for quality using the FASTX-Toolkit, and mapped using Bowtie, and counts per locus generated with BedTools in the Galaxy platform. Differential expression analysis was carried out in edgeR with significantly differentially expressed genes being identified as those with ≥|2| fold differential expression between ΔcsoR and wild type strains, and an FDR < 0.05. Results: We found that 223 genes were differentially expressed between the ΔcsoR and wild type strains, 52 induced and 71 repressed. Differential expression of 10 of these genes, 6 induced and 4 repressed, was confirmed by qRT-PCR using SYBR green methodology. The only copper responsive genes identified were those within the csoR operon: csoR, Rv0968, ctpV, Rv0970, suggesting that csoR may only regulate its own operon in response to copper. Genes in the RicR regulon, another copper responsive transcriptional regulator, were not significantly differentially expressed, but some of these copper inducible genes were slightly down regulated suggesting that copper levels may be lower in the mutant strain as compared to wild type. Notably, 44 of the 48 members of the dosR regulon, responsive to hypoxic and NO stress, were induced in the mutant vs wild type suggesting that csoR is necessary for maintaining homeostasis, likely through copper regulation, within the cell. Conclusions: We have shown that CsoR is likely only directly regulating its own operon in response to copper, however it is required to maintain homeostasis, preventing a hypoxia-type stress response in the absense of copper.
2016-11-01 | GSE74323 | GEO
Project description:We examined the whole-genome transcriptional response of E. faecalis wild-type (WT) and copy mutant cells exposed to non toxic Cu excess. The analysis was focused in those genes which changed significantly their expression levels in the Cu-treated cells when compared to their untreated counterparts. The results indicated that after 3 h at 0.5 mM CuSO4, WT cells exhibited a significant increment of Cu content and the induction of three genes of cop operon along with other 142 genes. The comparison with the copY mutant exposed to Cu showed an extensive overlapping of transcriptional changes suggesting that other transcription factors may be mediating the response to Cu. Associated manuscript The global response of Enterococcus faecalis to copper exposure
2011-02-14 | GSE20453 | GEO
Project description:We studied the transcriptome changes of Vibrio parahaemolyticus under normal culture condition and copper stress by RNA sequencing. The data showed that genes in copA and cusFABC operon were significantly upregulated by copper.
2024-08-01 | GSE268489 | GEO
Project description:Copper is essential for both innate and adaptive immune function and copper resistance has emerged as an important determinant of virulence of microbial pathogens. In the human pathogen Streptococcus pneumoniae (Spn), cytoplasmic copper resistance is mediated by an operon encoding the copper-responsive repressor CopY, CupA, of unknown function, and CopA, a copper effluxing P1B-type ATPase. We show that CupA is a novel cell membrane-anchored Cu(I) chaperone for CopA, and that a Cu(I)-binding competent, membrane-localized CupA, like CopA, is obligatory for copper resistance.
2013-05-24 | GSE39176 | GEO
Project description:Copper is both essential and toxic to living beings, which therefore tightly control its intracellular concentration. At the host-pathogen interface, copper is used by phagocytic cells to kill invading microorganisms. We investigated copper homeostasis in the whooping cough agent Bordetella pertussis, which lives in the human respiratory mucosa and has no environmental reservoir. B. pertussis has considerably streamlined copper homeostasis mechanisms relative to other Gram-negative bacteria. Its single remaining defense line against copper intoxication consists in a metallochaperone diverted for copper passivation and two enzymes involved in peroxide detoxification, which together fight two stresses encountered in phagolysosomes. The three proteins are encoded by an original, composite operon assembled in an environmental ancestor and which is under sensitive control by copper. Interestingly, this system appears to play a role in persistent infection in the nasal cavity of B. pertussis-infected mice. Combining responses to co-occurring stresses in a tailored operon reveals a new strategy adopted by a host-restricted pathogen to optimize survival at minimal energy expenditure.
2020-10-27 | GSE145049 | GEO
Project description:Copper is an essential component of cytochrome C oxidase (i.e. complex IV of the electron transport chain), and is thus critical for the survival of aerobic organisms. If copper is not properly regulated in the body however, it can be extremely cytotoxic and genetic mutations that compromise copper homeostasis result in severe clinical phenotypes. Understanding how cells maintain optimal copper levels is therefore highly relevant to human health. We found that addition of copper to culture medium leads to increased respiratory growth of yeast, a phenotype which we then systematically and quantitatively measured in 5050 homozygous diploid deletion strains using microarrays.
2013-05-23 | GSE47175 | GEO
Project description:The transition metal copper (Cu) is an essential element for all living organisms. In plants, Cu plays key roles in electron transport chains of chloroplasts and mitochondria, as well as in cell wall metabolism, ethylene perception, molybdenum cofactor synthesis and oxidative stress protection. Because of its physiological importance, suboptimal concentrations of Cu trigger a re-organization of metabolism to economize on Cu, and pronounced Cu deficiency causes severe growth reduction and defects in male fertility. However, when present in excess, Cu can be highly toxic. Therefore, Cu uptake, utilization and cellular concentrations are strictly regulated. A number of components of the Cu-homeostatic network of Arabidopsis have already been identified. However, the mechanisms that control responses of plant gene expression to Cu-deficiency are only partly understood. In Chlamydomonas reinhardtii, the transcription factor Crr1 is required for activating and/or repressing the expression of a number of genes in response to Cu deficiency. This protein contains a plant-specific DNA-binding domain (SBP domain), ankyrin repeats and a C-terminal cysteine-rich region with similarity to a Drosophila metallothionein (MT). In Arabidopsis, there is a family of 16 proteins with SBP domains named SPL family (SBP-like) of which a subset of proteins have been implicated in flowering time control and floral development. Among all of them, AtSPL7 is the most similar to Crr1 (27 % identity), and AtSPL1 (25 % identity), AtSPL12 (24 % identity) and AtSPL14 (23 % identity) share a common protein architecture. The goal of this work was to obtain a complete account of the response of the Arabidopsis thaliana transcriptome to Cu deficiency, as well as to determine the role of AtSPL7 in the transcriptional response to Cu deficiency. For this purpose, three independent experiments were carried out including Col-0 wild-type and spl7-2 mutant plants grown in Cu-sufficient and Cu-deficient hydroponic media, respectively. Root and shoot transcriptomes were established by RNA-Seq for quantitative comparisons. Sampling of root and shoot tissues of wild-type (WT, Col-0) and spl7-2 mutant plants (the mutant is knock-down for the transcription factor SPL7, which plays a key role in the transcriptional regulation of the copper deficiency responses) cultivated hydroponically in a modified Hoagland's solution under Cu-sufficient (control) and Cu-deficient conditions.
2013-10-14 | E-GEOD-24696 | biostudies-arrayexpress
Project description:Copper (Cu) homeostasis is critical to the health of most organisms, and is thus tightly regulated by several highly conserved processes. Using the unique genomic tools available in yeast, we have expanded current knowledge of these processes by identifying 237 genes important for Cu-dependent growth. 116 of these genes, when deleted, decreased Cu-dependent respiratory growth. The remaining 121 genes, when deleted, produced respiratory growth defects that were specifically rescued by addition of Cu. Among the genes identified by our screen are known regulators of copper homeostasis, genes required to maintain low vacuolar pH, and genes where evidence supporting a functional link with Cu has been heretofore lacking. Many genes identified are not only conserved in man, but also associated with diseases spanning a variety of clinical phenotypes. We demonstrate that the approved drug disulfiram rescues Cu-deficiencies of both environmental and genetic origin, thus underscoring a potential paradigm for treating the broad spectrum of Cu-related disease in man.
2013-05-19 | E-MEXP-3884 | biostudies-arrayexpress