Response of nor and nos contributes to Staphylococcus aureus virulence and metabolism.
Ontology highlight
ABSTRACT:
ORGANISM(S): Staphylococcus aureus
PROVIDER: GSE114147 | GEO | 2018/05/08
REPOSITORIES: GEO
Similar Datasets
Project description:Staphylococcus aureus causes a wide spectrum of disease, with the site and severity of infection dependent on virulence traits encoded within genetically distinct clonal complexes (CCs) and bacterial responses to host innate immunity. The production of nitric oxide (NO) by activated phagocytes is a major host response to which S. aureus metabolically adapts through multiple strategies that are conserved in all CCs, including an S. aureus nitric oxide synthase (Nos). Previous genome analysis of CC30, a lineage associated with chronic endocardial and osteoarticular infections, revealed a putative NO reductase (Nor) not found in other CCs that potentially contributes to NO resistance and clinical outcome. Here, we demonstrate that Nor has true nitric oxide reductase activity, with nor expression enhanced by NO stress and anaerobic growth. Furthermore, we demonstrate that nor is regulated by MgrA and SrrAB, which modulate S. aureus virulence and hypoxic response. Transcriptome analysis of the S. aureus UAMS-1, UAMS-1 Δnor, and UAMS-1 Δnos strains under NO stress and anaerobic growth demonstrates that Nor contributes to nucleotide metabolism and Nos to glycolysis. We demonstrate that Nor and Nos contribute to enhanced survival in the presence of human human polymorphonuclear cells and have organ-specific seeding in a tail vein infection model. Nor contributes to abscess formation in an osteological implant model. We also demonstrate that Nor has a role in S. aureus metabolism and virulence. The regulation overlap between Nor and Nos points to an intriguing link between regulation of intracellular NO, metabolic adaptation, and persistence in the CC30 lineage.IMPORTANCEStaphylococcus aureus can cause disease at most body sites, and illness spans asymptomatic infection to death. The variety of clinical presentations is due to the diversity of strains, which are grouped into distinct clonal complexes (CCs) based on genetic differences. The ability of S. aureus CC30 to cause chronic infections relies on its ability to evade the oxidative/nitrosative defenses of the immune system and survive under different environmental conditions, including differences in oxygen and nitric oxide concentrations. The significance of this work is the exploration of unique genes involved in resisting NO stress and anoxia. A better understanding of the functions that control the response of S. aureus CC30 to NO and oxygen will guide the treatment of severe disease presentations.
| S-EPMC6456865 | biostudies-literature
Project description:Response of nor and nos contributes to Staphylococcus aureus virulence and metabolism.
| PRJNA464411 | ENA
Project description:Staphylococcus aureus is a major human pathogen and resistant to numerous clinically used antibiotics. The first antibiotic developed for S. aureus infections was the nonribosomal petide secondary metabolite penicillin. We discovered cryptic nonribosomal peptide secondary metabolites, the aureusimines, made by S. aureus itself that are not antibiotics, but function as small molecule regulators of virulence factor expression. Using established rules and codes for nonribosomal peptide assembly we predicted these nonribosomal peptides, and used these predictions to identify them from S. aureus culture broths. Functional studies using global microarray and mouse bacteremia models established that the aureusimines control virulence factor expression and are necessary for productive infections. This is the first report of the aureusimines and has important implications for the treatment of drug resistant S. aureus. Targeting aureusimine synthesis may provide novel anti-infectives.
2010-07-01 | GSE21373 | GEO
Project description:From a Caenorhabditis elegans - S. aureus anti-infective screen, we identified benzimidazole derivative C162 as one of the potential anti-infective candidate that rescued the infected-nematodes from infection. This compound was found to exhibit anti-biofilm activity against S. aureus. To investigate the transcriptome profile of S. aureus in response to benzimidazole derivative C162, a genome-wide transcriptome analysis was performed on C162-treated S. aureus using the Affymetrix GeneChip S. aureus Genome Arrays. Our main interest is to look at the expression profiles of the biofilm-associated and virulence genes.
2018-02-13 | GSE84485 | GEO
Project description:Staphylococcus aureus nitric oxide synthase (saNOS) is a major contributor to virulence, stress resistance, and physiology, yet the specific mechanism(s) by which saNOS intersects with other known regulatory circuits is largely unknown. The SrrAB two-component system, which modulates gene expression in response to the reduced state of respiratory menaquinones, is a positive regulator of nos expression. Several SrrAB-regulated genes were also previously shown to be induced in an aerobically respiring nos mutant, suggesting a potential interplay between saNOS and SrrAB. Therefore, a combination of genetic, molecular, and physiological approaches was employed to characterize a nos srrAB mutant, which had significant reductions in the maximum specific growth rate and oxygen consumption when cultured under conditions promoting aerobic respiration. The nos srrAB mutant secreted elevated lactate levels, correlating with the increased transcription of lactate dehydrogenases. Expression of nitrate and nitrite reductase genes was also significantly enhanced in the nos srrAB double mutant, and its aerobic growth defect could be partially rescued with supplementation with nitrate, nitrite, or ammonia. Furthermore, elevated ornithine and citrulline levels and highly upregulated expression of arginine deiminase genes were observed in the double mutant. These data suggest that a dual deficiency in saNOS and SrrAB limits S. aureus to fermentative metabolism, with a reliance on nitrate assimilation and the urea cycle to help fuel energy production. The nos, srrAB, and nos srrAB mutants showed comparable defects in endothelial intracellular survival, whereas the srrAB and nos srrAB mutants were highly attenuated during murine sepsis, suggesting that SrrAB-mediated metabolic versatility is dominant in vivo.
| S-EPMC6346124 | biostudies-literature
Project description:Staphylococcus aureus is a major human pathogen and resistant to numerous clinically used antibiotics. The first antibiotic developed for S. aureus infections was the nonribosomal petide secondary metabolite penicillin. We discovered cryptic nonribosomal peptide secondary metabolites, the aureusimines, made by S. aureus itself that are not antibiotics, but function as small molecule regulators of virulence factor expression. Using established rules and codes for nonribosomal peptide assembly we predicted these nonribosomal peptides, and used these predictions to identify them from S. aureus culture broths. Functional studies using global microarray and mouse bacteremia models established that the aureusimines control virulence factor expression and are necessary for productive infections. This is the first report of the aureusimines and has important implications for the treatment of drug resistant S. aureus. Targeting aureusimine synthesis may provide novel anti-infectives. Commerically available S. aureus GeneChips (Affymetrix) were used to compare biological replicates of early and late exponential phase wild type (Newman) and aureusimine defective (ausA) organisms.
2010-07-30 | E-GEOD-21373 | biostudies-arrayexpress
Project description:Nitric oxide synthase (NOS) enzymes produce nitric oxide (NO), a highly reactive free radical capable of interacting with multiple cellular targets. Although saNOS contributes to Staphylococcus aureus virulence, as well as protection against exogenous oxidative stress and antimicrobials, the current mechanism behind these phenotypes is unknown. Here we report a previously-undescribed role for saNOS in modulating S. aureus physiology. When grown aerobically, endogenous reactive oxygen species (ROS) and superoxide levels were elevated in a S. aureus nos mutant. NO has been shown to slow respiration in other organisms, and likewise, comparison of respiratory dehydrogenase activity and membrane potential in wild-type, nos mutant, and complement strains suggested that saNOS-derived NO limits S. aureus aerobic respiration. Multiple transcriptional and metabolic changes were also observed in a S. aureus nos mutant, as assessed by RNAseq and targeted metabolomics analyses, respectively. Specifically, expression of genes associated with oxidative and nitrosative stress responses, anaerobic and lactate metabolism, and cytochrome biosynthesis and assembly were increased in the nos mutant relative to wild-type. Metabolites utilized to produce reducing equivalents by the right arm of the TCA cycle were depleted in a nos mutant (citrate and α-ketoglutarate), whereas fumarate and malate levels were increased relative to wild-type and complement strains. A significant reduction in lactate levels was also observed in the nos mutant. Collectively, these results support a model in which the absence of saNOS results in increased respiration and ROS accumulation, which may signal the cells to switch to an alternative lactate-based respiratory metabolism.
2017-07-10 | GSE77400 | GEO
Project description:CodY is a conserved regulator in gram-positive organisms described to repress metabolic genes mainly involved in nitrogen metabolism but also to control the expression of virulence genes in pathogens. We constructed codY gene-replacement mutants in three unrelated S. aureus strains (Newman, UAMS-1, RN1HG). codY mutants grew slower in a chemically defined medium compared to the wild type strains. However, only codY mutants were able to grow in medium lacking threonine. Excess of isoleucine resulted in growth inhibition in the wild type but not in the codY mutants indicating a role of isoleucine for CodY dependent repression of metabolic genes. The prototypic CodY-repressed operon ilvDBCleuABCilvA is preceded by a CodY-binding motif and repressed after up-shift with isoleucine and to a lesser extent guanidine. Transcription of the quorum sensing system agr followed a similar expression pattern. The codY dependent repression of agr is in line with the concomitant influence of CodY on typical agr regulated genes such as cap, spa fnbA and coa. However, transcriptional analysis revealed that most of these virulence genes (e.g. cap, fnbA, spa hla) are also regulated by CodY in an agr negative background. Microarray analysis revealed the large majority of codY-repressed genes are involved in amino-acid transport and metabolism, genes showing codY dependent activation were mainly involved in nucleotide transport and metabolism or virulence. In summary, CodY in S. aureus not only acts as repressor for genes involved in nitrogen metabolism but also contributes to virulence gene regulation by supporting as well as substituting agr function.
2008-11-07 | GSE12340 | GEO
Project description:CodY is a conserved regulator in gram-positive organisms described to repress metabolic genes mainly involved in nitrogen metabolism but also to control the expression of virulence genes in pathogens. We constructed codY gene-replacement mutants in three unrelated S. aureus strains (Newman, UAMS-1, RN1HG). codY mutants grew slower in a chemically defined medium compared to the wild type strains. However, only codY mutants were able to grow in medium lacking threonine. Excess of isoleucine resulted in growth inhibition in the wild type but not in the codY mutants indicating a role of isoleucine for CodY dependent repression of metabolic genes. The prototypic CodY-repressed operon ilvDBCleuABCilvA is preceded by a CodY-binding motif and repressed after up-shift with isoleucine and to a lesser extent guanidine. Transcription of the quorum sensing system agr followed a similar expression pattern. The codY dependent repression of agr is in line with the concomitant influence of CodY on typical agr regulated genes such as cap, spa fnbA and coa. However, transcriptional analysis revealed that most of these virulence genes (e.g. cap, fnbA, spa hla) are also regulated by CodY in an agr negative background. Microarray analysis revealed the large majority of codY-repressed genes are involved in amino-acid transport and metabolism, genes showing codY dependent activation were mainly involved in nucleotide transport and metabolism or virulence. In summary, CodY in S. aureus not only acts as repressor for genes involved in nitrogen metabolism but also contributes to virulence gene regulation by supporting as well as substituting agr function. The microarray was manufactured by in situ synthesis of 10'807 long oligonucleotide probes , selected as previously described (Charbonnier, 2005). It covers >98% of all ORFs annotated in strains N315 and Mu50 , MW2, COL , NCTC8325, USA300 , MRSA252 an MSSA476 including their respective plasmids.
2008-11-06 | E-GEOD-12340 | biostudies-arrayexpress
Project description:This work aimed to investigate the metabolic changes of epithelial cell metabolism during S. aureus infection. We revealed that persistent S. aureus survived in epithelial cells by modulating the cellular pathways of one carbon pool by folate. These results highlight the persistence mechanisms of S. aureus survived in epithelial cells by regulation of cellular metabolism, shedding light on the development of intervention strategies to combat S. aureus associated infections.
2021-05-12 | GSE174235 | GEO