Prevalence of<i>agr</i>Dysfunction among Colonizing<i>Staphylococcus aureus</i>Strains

Shopsin, Bo; Drlica-Wagner, Alex; Mathema, Barun; Adhikari, Rajan P.; Kreiswirth, Barry N.; Novick, Richard P.

doi:10.1086/592051

Cited by 118 publications

(106 citation statements)

References 14 publications

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“…Because delta-hemolysin is encoded by hld within the agr locus and is derived from the translation of RNAIII, the effector of agr regulon, its production is a marker of agr function (36). Loss of agr function has been linked to attenuated virulence (48) and has global effects on bacterial phenotypes (14,40,46) and increased mortality among S. aureus bacteremia patients (39). However, we found no evidence in the current investigation that agr dysfunction is associated with the outcome of HAP.…”

Section: Discussionmentioning

confidence: 99%

Presence of Genes Encoding Panton-Valentine Leukocidin Is Not the Primary Determinant of Outcome in Patients with Hospital-Acquired Pneumonia Due to Staphylococcus aureus

et al. 2012

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The impact of Panton-Valentine leukocidin (PVL) on the outcome intested, (ii) presence of specific bacterial clone, (iii) levels of alphahemolysin, or (iv) delta-hemolysin production were identified. This study suggests that neither pvl presence nor in vitro level of alpha-hemolysin production is the primary determinant of outcome among patients with HAP caused by S. aureus. The Panton-Valentine leukocidin (PVL) is a bacteriophageassociated, bicomponent cytotoxin produced by some strains of Staphylococcus aureus. PVL induces host cell necrosis and apoptosis by producing pores in the cell membranes of neutrophils and other infected cells. The presence of PVL and the genetic elements coding for its production (two contiguous, cotranscribed genes, lukS and lukF, here referred to as pvl) has been strongly associated with a severe necrotizing pneumonia (13, 15). Although controversy persists, there is evidence that PVL is associated with severe disease in community-acquired pneumonia (CAP) due to S. aureus both in clinical reports (13, 15) and in some (10, 22), but not all (3,20,30,49), in vivo model systems. However, the studies on the association between PVL and clinical outcomes in hospitalacquired pneumonia (HAP), a distinct clinical entity from CAP, are limited.Hospital-acquired pneumonia is the leading cause of morbidity and mortality from nosocomial infections (9), and S. aureus is the leading cause of HAP in U.S. hospitals (12,28,34). In the current study, we tested the hypothesis that pvl presence in S. aureus isolates causing HAP was associated with a worse clinical outcome than the outcome of HAP caused by pvl-negative S. aureus counterparts. To test this hypothesis, we made use of a large international cohort of S. aureus isolates from patients with HAP. These isolates were collected in two identically designed phase III clinical trials for S. aureus HAP. MATERIALS AND METHODSPatients and study settings. The ATTAIN (Assessment of Telavancin for Hospital-Acquired Pneumonia) clinical trials were two identical phase III, randomized, double-blinded, parallel-group, multinational trials (ClinicalTrials.gov identifiers NCT00107952 and NCT00124020) studying the efficacy and safety of intravenous telavancin versus vancomycin for the treatment of hospital-acquired pneumonia (HAP) with a focus on patients with infections due to methicillin-resistant S. aureus (MRSA) (35). Following randomization, patients were treated for 7 to 21 days with the study drug. From January 2005 to June 2007, a total of 1,503 patients were enrolled from 235 clinical centers in 38 countries. Patients were included in the current study if all of the following criteria were met: (i) inclusion in the modified all treated (MAT) population (n ϭ 1,089), (ii) had monomicrobial infection with S. aureus at baseline, and (iii) had a clinical response of either "cure" or "failure" for the test-of-cure analysis. All patients or their legal guardian provided written informed consent. This study was approved by Duke University Medical Center Institutio...

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Section: Discussionmentioning

confidence: 99%

Presence of Genes Encoding Panton-Valentine Leukocidin Is Not the Primary Determinant of Outcome in Patients with Hospital-Acquired Pneumonia Due to Staphylococcus aureus

et al. 2012

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“…For example, a major regulator of S. aureus cytotoxicity and hemolysis, accessory gene regulator (agr), is known to be mutated in a proportion of bacteria recovered from within human host cells (20)(21)(22). Such mutants have also been noted among hospital-derived isolates of virulent clones of S. aureus (23).…”

Section: Significancementioning

confidence: 99%

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Das

Lindemann

Young

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Staphylococcus aureus is a major bacterial pathogen, which causes severe blood and tissue infections that frequently emerge by autoinfection with asymptomatically carried nose and skin populations. However, recent studies report that bloodstream isolates differ systematically from those found in the nose and skin, exhibiting reduced toxicity toward leukocytes. In two patients, an attenuated toxicity bloodstream infection evolved from an asymptomatically carried high-toxicity nasal strain by loss-of-function mutations in the gene encoding the transcription factor repressor of surface proteins (rsp). Here, we report that rsp knockout mutants lead to global transcriptional and proteomic reprofiling, and they exhibit the greatest signal in a genome-wide screen for genes influencing S. aureus survival in human cells. This effect is likely to be mediated in part via SSR42, a long-noncoding RNA. We show that rsp controls SSR42 expression, is induced by hydrogen peroxide, and is required for normal cytotoxicity and hemolytic activity. Rsp inactivation in laboratory- and bacteremia-derived mutants attenuates toxin production, but up-regulates other immune subversion proteins and reduces lethality during experimental infection. Crucially, inactivation of rsp preserves bacterial dissemination, because it affects neither formation of deep abscesses in mice nor survival in human blood. Thus, we have identified a spontaneously evolving, attenuated-cytotoxicity, nonhemolytic S. aureus phenotype, controlled by a pleiotropic transcriptional regulator/noncoding RNA virulence regulatory system, capable of causing S. aureus bloodstream infections. Such a phenotype could promote deep infection with limited early clinical manifestations, raising concerns that bacterial evolution within the human body may contribute to severe infection.

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“…taphylococcus aureus is a major human pathogen, responsible for 1% of all hospital admissions and leading to an estimated cost of $9.5 billion per year in the United States alone (1)(2)(3)(4). Infections caused by S. aureus range from relatively mild boils and infected skin wounds to those with high mortality rates, such as bacteremia, infective endocarditis, and toxic shock.…”

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confidence: 99%

Cooperation, Quorum Sensing, and Evolution of Virulence in Staphylococcus aureus

et al. 2014

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bThe virulence and fitness in vivo of the major human pathogen Staphylococcus aureus are associated with a cell-to-cell signaling mechanism known as quorum sensing (QS). QS coordinates the production of virulence factors via the production and sensing of autoinducing peptide (AIP) signal molecules by the agr locus. Here we show, in a wax moth larva virulence model, that (i) QS in S. aureus is a cooperative social trait that provides a benefit to the local population of cells, (ii) agr mutants, which do not produce or respond to QS signal, are able to exploit the benefits provided by the QS of others ("cheat"), allowing them to increase in frequency when in mixed populations with cooperators, (iii) these social interactions between cells determine virulence, with the host mortality rate being negatively correlated to the percentage of agr mutants ("cheats") in a population, and (iv) a higher within-host relatedness (lower strain diversity) selects for QS and hence higher virulence. Our results provide an explanation for why agr mutants show reduced virulence in animal models but can be isolated from infections of humans. More generally, by providing the first evidence that QS is a cooperative social behavior in a Gram-positive bacterium, our results suggest convergent, and potentially widespread, evolution for signaling to coordinate cooperation in bacteria. Staphylococcus aureus is a major human pathogen, responsible for 1% of all hospital admissions and leading to an estimated cost of $9.5 billion per year in the United States alone (1-4). Infections caused by S. aureus range from relatively mild boils and infected skin wounds to those with high mortality rates, such as bacteremia, infective endocarditis, and toxic shock. S. aureus infections can be difficult to treat because of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA), which are resistant to beta-lactam antibiotics. Globally, MRSA infection rates are increasing (2, 5, 6).The virulence and growth in vivo of S. aureus depend upon quorum sensing (QS) via the accessory gene regulator (agr) locus (1,7,8). Cells release a small autoinducing peptide (AIP), the accumulation of which induces the production and secretion of both more AIP and a range of virulence factors. These virulence factors include hemolysins ␣, ␤, ␦, and ␥, toxic shock syndrome toxin (TSST), enterotoxins, Panton-Valentine leukocidin (PVL), and exfoliatins A and B (8-10). At high cell densities, or when cells are enclosed in small spaces, the agr system leads to positive feedback in the production of AIP and a significant increase in the production of virulence factors (11-15).It is commonly assumed that QS is a cooperative social trait, in which the benefits of virulence factors are shared between the local population of cells and their production is coordinated across cells via QS (16, 17). However, there has been no empirical demonstration that QS in S. aureus, or any other Gram-positive bacteria, is a cooperative social trait (see Discussion). Evidence that QS...

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Prevalence ofagrDysfunction among ColonizingStaphylococcus aureusStrains

Cited by 118 publications

References 14 publications

Presence of Genes Encoding Panton-Valentine Leukocidin Is Not the Primary Determinant of Outcome in Patients with Hospital-Acquired Pneumonia Due to Staphylococcus aureus

Presence of Genes Encoding Panton-Valentine Leukocidin Is Not the Primary Determinant of Outcome in Patients with Hospital-Acquired Pneumonia Due to Staphylococcus aureus

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Cooperation, Quorum Sensing, and Evolution of Virulence in Staphylococcus aureus

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