Pharmacologic disruption of agr quorum sensing in Staphylococcus aureus promotes host defense against skin and soft tissue infections
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ABSTRACT:
ORGANISM(S): Staphylococcus aureus subsp. aureus USA300 Staphylococcus aureus
PROVIDER: GSE52978 | GEO | 2017/02/09
SECONDARY ACCESSION(S): PRJNA230620
REPOSITORIES: GEO
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Project description:RNAseq of exponentially growing cultures of the four agr prototype strains used in the study to investigate if differential expression of regulators interacting with the agr system could explain the differences in AIP sensitivity. Abstract Staphylococcus aureus both colonizes humans and causes severe virulent infections. Virulence is regulated by the agr quorum sensing system and its autoinducing peptide (AIP), with dynamics at the single-cell level across four agr-types – each defined by distinct AIP sequences and capable of cross-inhibition – remaining elusive. Employing microfluidics, time-lapse microscopy, and deep-learning image analysis, we uncovered significant differences in AIP sensitivity among agr-types. We observed bimodal agr activation, attributed to intergenerational phenotypic stability and influenced by AIP concentration. Upon AIP stimulation, agr III showed AIP insensitivity, while agr II exhibited increased sensitivity and prolonged generation time. Beyond expected cross-inhibition of agr I by heterologous AIP II and III, the presumably cross-activating AIP IV also inhibited agr I. Community interactions across different agr-type pairings revealed four main patterns: stable or switched dominance, and delayed or stable dual activation, influenced by community characteristics. These insights underscore the potential of personalized treatment strategies considering virulence and genetic diversity.
2024-03-05 | E-MTAB-13859 | biostudies-arrayexpress
Project description:The agr quorum-sensing system clearly links Staphylococcus aureus metabolism to virulence, but little is known about how agr alters metabolism to affect cell survival during severe stress. Recently, we reported that agr activity increases survival of bacteria during treatment with lethal concentrations of H2O2, a crucial host defense against S. aureus. Here we report that protection by agr extends to growth resumption during the exit from stationary phase. The data indicate that the agr functionality of a cell’s ancestor affects stress-resiliency after resuming growth. Protection against killing by H2O2 depended on the agr effector molecule RNAIII and Rot, a transcription factor targeted by RNAIII. Expression data revealed that Δagr strains shift to fermentation, suggesting that agr promotes aerobic respiration. Epistasis between mutation of agr and sortase, which anchors surface proteins to the cell wall, suggested that reduced killing by H2O2 of wild-type agr strains acts through down-regulation of surface proteins that perturb respiration. Respiration generates reactive oxygen species (ROS), moderate amounts of which can protect from subsequent challenge by lethal concentrations, explaining agr-mediated protection against subsequent lethal H2O2 doses. Increased survival of wild-type agr cells in response to H2O2 required sodA, which dismutates O2- to H2O2, suggesting that sodA helps induce the low, protective levels of ROS triggered by agr. Additionally, detrimental effects of the Δagr mutation require ahpC, which functions to decrease the intracellular level of H2O2. Deletion of ahpC or sortase attenuated neutrophil-mediated killing of Δagr strains, demonstrating the importance of priming in anticipation of impending immune attack.
2023-06-20 | GSE206916 | GEO
Project description:The Staphylococcus aureus accessory gene regulator (agr) is a prototype quorum-sensing system in Gram-positive bacteria and a paradigmatic example of gene regulation by a small regulatory RNA, RNAIII. Using genome-wide transcriptional profiling in the community-associated methicillin-resistant (CA-MRSA) strain MW2, we demonstrate here that in contrast to the current model of target gene regulation by agr, a large subset of agr-regulated genes is controlled independently of RNAIII. This group comprised predominantly metabolism genes, whereas virulence factors were mostly controlled by RNAIII. Remarkably, the phenol-soluble modulin (PSM) leukocidin genes were the only virulence determinants under RNAIII-independent control, emphasizing their exceptional role in S. aureus physiology and pathogenesis. Of note, PSM promoters bound the AgrA response regulator protein, previously believed to interact exclusively with agr promoters, explaining the exceptionally strict control of PSMs by agr. Our results suggest that virulence factor control is a secondary acquisition of the agr regulon, which evolved by development of RNAIII around the mRNA of the PSM d-toxin, exemplifying how gene control via a small regulatory RNA may be linked to a pre-established regulatory circuit. In addition to elucidating agr control in CA-MRSA, which revealed features potentially crucial for CA-MRSA pathogenesis, our study establishes a novel two-level model of cell-density dependent gene regulation in S. aureus and gives important insight into the connection of metabolism and virulence control in this leading opportunistic pathogen. Keywords: Wild type control vs mutant Wild type in triplicate is compared to mutant in triplicate totalling 27 samples
2010-05-14 | E-GEOD-10165 | biostudies-arrayexpress
Project description:The Staphylococcus aureus accessory gene regulator (agr) is a prototype quorum-sensing system in Gram-positive bacteria and a paradigmatic example of gene regulation by a small regulatory RNA, RNAIII. Using genome-wide transcriptional profiling in the community-associated methicillin-resistant (CA-MRSA) strain MW2, we demonstrate here that in contrast to the current model of target gene regulation by agr, a large subset of agr-regulated genes is controlled independently of RNAIII. This group comprised predominantly metabolism genes, whereas virulence factors were mostly controlled by RNAIII. Remarkably, the phenol-soluble modulin (PSM) leukocidin genes were the only virulence determinants under RNAIII-independent control, emphasizing their exceptional role in S. aureus physiology and pathogenesis. Of note, PSM promoters bound the AgrA response regulator protein, previously believed to interact exclusively with agr promoters, explaining the exceptionally strict control of PSMs by agr. Our results suggest that virulence factor control is a secondary acquisition of the agr regulon, which evolved by development of RNAIII around the mRNA of the PSM d-toxin, exemplifying how gene control via a small regulatory RNA may be linked to a pre-established regulatory circuit. In addition to elucidating agr control in CA-MRSA, which revealed features potentially crucial for CA-MRSA pathogenesis, our study establishes a novel two-level model of cell-density dependent gene regulation in S. aureus and gives important insight into the connection of metabolism and virulence control in this leading opportunistic pathogen. Keywords: Wild type control vs mutant
2009-01-05 | GSE10165 | GEO
Project description:The agr quorum-sensing system clearly links Staphylococcus aureus metabolism to virulence, but little is known about how agr alters metabolism to affect cell survival during severe stress. Recently, we reported that agr activity increases survival of bacteria during treatment with lethal concentrations of H2O2, a crucial host defense against S. aureus. Here we report that protection by agr extends to growth resumption during the exit from stationary phase. The data indicate that the agr functionality of a cell’s ancestor affects stress-resiliency after resuming growth. Protection against killing by H2O2 depended on the agr effector molecule RNAIII and Rot, a transcription factor targeted by RNAIII. Expression data revealed that Δagr strains shift to fermentation, suggesting that agr promotes aerobic respiration. Epistasis between mutation of agr and sortase, which anchors surface proteins to the cell wall, suggested that reduced killing by H2O2 of wild-type agr strains acts through down-regulation of surface proteins that perturb respiration. Respiration generates reactive oxygen species (ROS), moderate amounts of which can protect from subsequent challenge by lethal concentrations, explaining agr-mediated protection against subsequent lethal H2O2 doses. Increased survival of wild-type agr cells in response to H2O2 required sodA, which dismutates O2- to H2O2, suggesting that sodA helps induce the low, protective levels of ROS triggered by agr. Additionally, detrimental effects of the Δagr mutation require ahpC, which functions to decrease the intracellular level of H2O2. Deletion of ahpC or sortase attenuated neutrophil-mediated killing of Δagr strains, demonstrating the importance of priming in anticipation of impending immune attack.
2023-06-20 | GSE206889 | GEO
Project description:The success of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) as pathogens is due to a combination of antibiotic resistance with high virulence. However, evolution of the exceptional virulence potential of CA-MRSA is not understood. Our previous study indicated that differential gene expression contributes substantially to this process. Thus, we here investigated the role of the pivotal virulence gene regulatory system agr in the most prevalent CA-MRSA strain USA300. Using a mouse subcutaneous infection model, we show that agr is essential for the development of CA-MRSA skin infections, the most frequent manifestation of disease caused by CA-MRSA. Furthermore, genome-wide analysis of gene expression revealed significant differences in agr-dependent virulence gene regulation between CA-MRSA, HA-MRSA, and laboratory strains. Our findings demonstrate that agr functionality is critical for CA-MRSA disease and indicate that an adaptation of the agr regulon to optimize expression of a broad set of virulence determinants may have contributed to the evolution of exceptionally pronounced virulence of CA-MRSA strains. Keywords: wild type vs mutant Wild type vs mutant agr strains.
2011-03-29 | E-GEOD-18793 | biostudies-arrayexpress
Project description:The success of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) as pathogens is due to a combination of antibiotic resistance with high virulence. However, evolution of the exceptional virulence potential of CA-MRSA is not understood. Our previous study indicated that differential gene expression contributes substantially to this process. Thus, we here investigated the role of the pivotal virulence gene regulatory system agr in the most prevalent CA-MRSA strain USA300. Using a mouse subcutaneous infection model, we show that agr is essential for the development of CA-MRSA skin infections, the most frequent manifestation of disease caused by CA-MRSA. Furthermore, genome-wide analysis of gene expression revealed significant differences in agr-dependent virulence gene regulation between CA-MRSA, HA-MRSA, and laboratory strains. Our findings demonstrate that agr functionality is critical for CA-MRSA disease and indicate that an adaptation of the agr regulon to optimize expression of a broad set of virulence determinants may have contributed to the evolution of exceptionally pronounced virulence of CA-MRSA strains. Keywords: wild type vs mutant
2011-03-29 | GSE18793 | GEO
Project description:Functionality of the accessory gene regulator (agr) quorum sensing system is an important switch promoting either acute or chronic infections, mediated by the notorious opportunistic human and veterinary pathogen Staphylococcus aureus. Spontaneous alterations of the agr system are known to frequently occur in human healthcare-associated S. aureus lineages. However, data on agr integrity and function are sparse regarding other major lineages. Here we report on the agr system functionality and activity level in mecC-carrying methicillin resistant S. aureus (MRSA) of various animal origins (n=33) in Europe together with closely related isolates of human patients (n=12). Whole genome analysis assigned all isolates to four clonal complexes (CC) with distinct agr types (CC599 agr I, CC49 agr II, CC130 agr III and CC1943 agr IV). Different levels of agr functionality were detected by use of different phenotype assays and proteomics for isolates of each CC, including completely non-functional variants. Genomic comparison of the agr I-IV encoding regions revealed that variants of AgrA and AgrC were associated with these phenotype changes, especially among the isolates of pet- and wild animal origin. Since a role in adaptation is most likely when genomic changes occur independently in divergent lineages, agr variation might foster viability and niche adjustment capacities of rare MRSA lineages.
2021-09-09 | PXD016486 | Pride
Project description:The study aims to compare gene expression patterns of Staphyloccoccus aureus USA300 wild type (reference) vs USA300 agr knockout(query). The agr quorum sensing system is an important regulator of density dependent gene expression. To determine the role of agr in USA300 virulence a agr mutant was constructed and differential gene expression compared to the parental wildtype.
2011-04-08 | GSE26254 | GEO
Project description:S. aureus response to agr operon and a SAUSA300_1984 deletion.
2019-03-14 | GSE121625 | GEO