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A point mutation in the agr locus caused previously reported phenotypes in Staphylococcus aureus pneumonia

ABSTRACT: The role of Panton‐Valentine leukocidin (PVL) in Staphylococcus aureus pathogenesis is controversial. Here, we show that an unintended point mutation in the agr P2 promoter of S.aureus caused the phenotypes in gene regulation and murine pneumonia attributed to PVL by Labandeira‐Rey et al. (Science 315:1130‐3, 2007). In agreement with previous studies that failed to detect similar effects of PVL using community‐associated methicillin‐resistant S. aureus strains, we found no significant impact of PVL on gene expression or pathogenesis after we repaired the mutation. These findings further contribute to the idea that PVL does not have a major impact on S. aureus pathogenesis and resolve debate about its role in murine infection models. Moreover, our results demonstrate that a single nucleotide polymorphism in an intergenic region can dramatically impact bacterial physiology and virulence. Finally, our work emphasizes the need to frequently evaluate the integrity of the S. aureus agr locus.

ORGANISM(S): Staphylococcus aureus subsp. aureus USA300 Staphylococcus aureus

PROVIDER: GSE14394 | GEO | 2009/12/31

SECONDARY ACCESSION(S): PRJNA111367

REPOSITORIES: GEO

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A point mutation in the agr locus caused previously reported phenotypes in Staphylococcus aureus pneumonia

Project description:The role of Pantonâ??Valentine leukocidin (PVL) in Staphylococcus aureus pathogenesis is controversial. Here, we show that an unintended point mutation in the agr P2 promoter of S.aureus caused the phenotypes in gene regulation and murine pneumonia attributed to PVL by Labandeiraâ??Rey et al. (Science 315:1130â??3, 2007). In agreement with previous studies that failed to detect similar effects of PVL using communityâ??associated methicillinâ??resistant S. aureus strains, we found no significant impact of PVL on gene expression or pathogenesis after we repaired the mutation. These findings further contribute to the idea that PVL does not have a major impact on S. aureus pathogenesis and resolve debate about its role in murine infection models. Moreover, our results demonstrate that a single nucleotide polymorphism in an intergenic region can dramatically impact bacterial physiology and virulence. Finally, our work emphasizes the need to frequently evaluate the integrity of the S. aureus agr locus. 7 hour growth, with 5 different strain comparisons

2010-05-16 | E-GEOD-14394 | biostudies-arrayexpress

Comparison of S. aureus PVL-positive and PVL-negative isogenic strains in exponential and stationary phase of growth

Project description:The Staphylococcus aureus Panton Valentine leukocidin (PVL) is a pore-forming toxin secreted by strains epidemiologically associated with the current outbreak of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and with the often lethal necrotizing pneumonia. To investigate the role of PVL in pulmonary disease, we tested the pathogenicity of clinical isolates, isogenic PVL-negative and PVL-positive S. aureus strains, as well as purified PVL, in a mouse acute pneumonia model. Here we show that PVL is sufficient to cause pneumonia and that the expression of this leukotoxin induces global changes in transcriptional levels of genes encoding secreted and cell-wall-anchored staphylococcal proteins, including the lung inflammatory factor staphylococcal protein A (Spa). Keywords: comparative transcription profile in the presence or absence of PVL toxin

2007-02-13 | GSE6985 | GEO

Panton-Valentine Leukocidin Does Not Impact Virulence of Community-associated MRSA

2008-09-12 | GSE8677 | GEO

Neutrophils from patients with recurring Panton-Valentine Leukocidin-positive Staphylococcus aureus infections are more sensitive to PVL induced NETosis

Project description:Panton-Valentine Leukocidin (PVL) is a Staphylococcus aureus toxin that binds to and kills human neutrophils resulting in the formation of neutrophil extracellular traps. A subset of individuals colonized with PVL expressing S. aureus suffer from recurring infections. We found that neutrophils from affected individuals display increased spontaneous NET formation after isolation, and increased sensitivity to killing by PVL. Compared to healthy controls, the expression of the target receptors for PVL, CD45 and C5L2, but not CD88, was increased in these patients, and the expression correlated to the amount of PVL-induced NETs produced. NADPH-oxidase activity was not important for PVL induced NETosis as neutrophils from CGD patients produced NETs in response to PVL. Through NET proteome analysis we identified that the protein content of PVL induced NETs is different from mitogen induced NETs. The abundance of the antimicrobial proteins LL37, myeloperoxidase, azurocidin, and proteinase 3 was lower on PVL NETs and PVL-induced NETs were deficient in killing Staphylococcus aureus. Neutrophils from patients that suffer from recurring PVL-positive infections may be more sensitive to PVL-induced NETosis, impairing their ability to combat the infection.

2023-11-23 | PXD025702 | Pride

Characterization and comparison of two epidemic community-associated methicillin resistant Staphylococcus aureus clones of ST59 lineage

Project description:Comparing two subclones (Taiwan clone and Asian-Pacific clone) of CA-MRSA ST59. The Taiwan clone carries the Panton-Valentine leukocidin (PVL) genes, the staphylococcal chromosomal cassette mec (SCCmec) VT and is frequently isolated from patients with severe disease. The Asian-Pacific clone is PVL-negative, carries SCCmec IV, and is a frequent colonizer of healthy children.

2012-05-31 | E-MEXP-3627 | biostudies-arrayexpress

Panton-Valentine Leukocidin Does Not Impact Virulence of Community-associated MRSA

Project description:Panton-valentine leukocidin (PVL) has been linked to worldwide emergence of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) -- its role in virulence in unclear. Here we show that PVL had no effect on global gene expression of prominent CA-MRSA strains nor did it affect bacterial clearance from lungs, spleen and kidneys in a highly discriminatory rabbit bacteremia model. These findings negate a large body of epidemiological research that implicated PVL in CA-MRSA virulence. Keywords: mutant vs wild type in 2 different growth phases grown in 2 different medias Wild type USA 300 (strain SF8300), wild type USA 400 (strain MW2) were compared against their respective PVL isogenic knock out strains. Strains were compared at both mid-exponential and stationary phase and grown in both TSB and CCY to determine if PVL plays a role in gene regulation under these conditions.

2010-06-19 | E-GEOD-8677 | biostudies-arrayexpress

Evolution of virulence control by the staphylococcal agr quorum-sensing regulator

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

Evolution of virulence control by the staphylococcal agr quorum-sensing regulator

2009-01-05 | GSE10165 | GEO

Sublytic concentrations of Staphylococcus aureus Panton-Valentine leukocidin alter human polymorphonuclear leukocyte gene expression and enhance bactericidal capacity.

Project description:Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are often caused by strains encoding Panton-Valentine leukocidin (PVL). PVL can cause lysis of polymorphonuclear leukocytes (PMNs) and other myeloid cells in vitro, a function considered widely as the primary means by which PVL might contribute to disease. However, at sublytic concentrations PVL can function as a PMN agonist. To better understand this phenomenon, we investigated the ability of PVL to alter human PMN function. PMNs exposed to PVL had enhanced capacity to produce superoxide in response to N-formyl-methionyl-leucyl-phenylalanine (fMLF), but unlike priming by lipopolysaccharide, this response did not require Toll-like receptor signal transduction. On the other hand, there was subcellular redistribution of NADPH oxidase components in PMNs following exposure of these cells to PVL - a finding consistent with priming. Priming of PMNs with other agonists such as IL-8 or GM-CSF altered the ability PVL to cause formation of pores in the plasma membranes of these cells. Microarray analysis revealed significant changes in the human PMN transcriptome following exposure to PVL, including up-regulation of molecules that regulate the inflammatory response. Consistent with the microarray data, mediators of the inflammatory response were released from PMNs after stimulation with PVL. We conclude that exposure of human PMNs to sublytic concentrations of PVL elicits a proinflammatory response that is regulated in part at the level of gene expression. We propose that PVL-mediated priming of PMNs enhances the host innate immune response. time series of PMN's non treated vs PVL treated vs iPVL treated

2012-09-06 | E-GEOD-33939 | biostudies-arrayexpress

Sublytic concentrations of Staphylococcus aureus Panton-Valentine leukocidin alter human polymorphonuclear leukocyte gene expression and enhance bactericidal capacity.

2012-09-06 | GSE33939 | GEO

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