Effects of Neutrophils on Cefazolin Activity and Penicillin-Binding Proteins in
            <i>Staphylococcus aureus</i>
            Abscesses

Bamberger, David M.; Herndon, Betty; Fitch, Jeffrey; Florkowski, Aaron; Parkhurst, Vera

doi:10.1128/aac.46.9.2878-2884.2002

Cited by 20 publications

(22 citation statements)

References 19 publications

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“…The rat tissue cage infection model has been described previously (8,30). Briefly, a perforated sterilized pingpong ball is surgically implanted into the peritoneal cavity of an adult male Sprague-Dawley rat and allowed to encapsulate for 4 to 5 weeks.…”

Section: Methodsmentioning

confidence: 99%

Dps and DpsL Mediate SurvivalIn VitroandIn Vivoduring the Prolonged Oxidative Stress Response in Bacteroides fragilis

2015

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Bacteroides fragilis is a Gram-negative anaerobe and member of the human intestinal tract microbiome, where it plays many beneficial roles. However, translocation of the organism to the peritoneal cavity can lead to peritonitis, intra-abdominal abscess formation, bacteremia, and sepsis. During translocation, B. fragilis is exposed to increased oxidative stress from the oxygenated tissues of the peritoneal cavity and the immune response. In order to survive, B. fragilis mounts a robust oxidative stress response consisting of an acute and a prolonged oxidative stress (POST) response. This report demonstrates that the ability to induce high levels of resistance to tert-butyl hydroperoxide (tBOOH) after extended exposure to air can be linked to the POST response. Disk diffusion assays comparing the wild type to a ⌬dps mutant and a ⌬dps ⌬bfr mutant showed greater sensitivity of the mutants to tBOOH after exposure to air, suggesting that Dps and DpsL play a role in the resistance phenotype. Complementation studies with dps or bfr (encoding DpsL) restored tBOOH resistance, suggesting a role for both of these ferritin-family proteins in the response. Additionally, cultures treated with the iron chelator dipyridyl were not killed by tBOOH, indicating Dps and DpsL function by sequestering iron to prevent cellular damage. An in vivo animal model showed that the ⌬dps ⌬bfr mutant was attenuated, indicating that management of iron is important for survival within the abscess. Together, these data demonstrate a role for Dps and DpsL in the POST response which mediates survival in vitro and in vivo. IMPORTANCEB. fragilis is the anaerobe most frequently isolated from extraintestinal opportunistic infections, but there is a paucity of information about the factors that allow this organism to survive outside its normal intestinal environment. This report demonstrates that the iron storage proteins Dps and DpsL protect against oxidative stress and that they contribute to survival both in vitro and in vivo. Additionally, this work demonstrates an important role for the POST response in B. fragilis survival and provides insight into the complex regulation of this response. Bacteroides spp. are members of the normal intestinal microbiome of humans. The intestine is a consistent and favorable environment that provides continuous access to nutrient sources for these strictly anaerobic organisms. Bacteroides spp. play many important roles in maintaining a healthy intestinal tract, such as polysaccharide degradation, protection of the gut epithelia from colonization by pathogenic bacteria, development of the intestinal tract, maturation of the mucosal and systemic immune systems, and transformation of toxic and mutagenic compounds (1-4). However, when the integrity of the intestinal wall is breached due to trauma, abdominal surgery, or diseases such as appendicitis, perforated ulcer, diverticulitis, and colon cancer, translocation of the normal flora into the peritoneal cavity can result in peritonitis and establishment of an intr...

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Section: Methodsmentioning

confidence: 99%

Dps and DpsL Mediate SurvivalIn VitroandIn Vivoduring the Prolonged Oxidative Stress Response in Bacteroides fragilis

2015

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“…The tissue cage infection model has been described previously (27,28). Briefly, a perforated, sterilized ping pong ball was surgically implanted into the peritoneal cavity of an adult male SpragueDawley rat and allowed to encapsulate for 4-5 wk.…”

Section: Methodsmentioning

confidence: 99%

Efficient utilization of complex N-linked glycans is a selective advantage for Bacteroides fragilis in extraintestinal infections

Cao

Rocha

Smith

2014

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

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Bacteroides fragilis is the most common anaerobe isolated from clinical infections, and in this report we demonstrate a characteristic of the species that is critical to their success as an opportunistic pathogen. Among the Bacteroides spp. in the gut, B. fragilis has the unique ability of efficiently harvesting complex N-linked glycans from the glycoproteins common to serum and serous fluid. This activity is mediated by an outer membrane protein complex designated as Don. Using the abundant serum glycoprotein transferrin as a model, it has been shown that B. fragilis alone can rapidly and efficiently deglycosylate this protein in vitro and that transferrin glycans can provide the sole source of carbon and energy for growth in defined media. We then showed that transferrin deglycosylation occurs in vivo when B. fragilis is propagated in the rat tissue cage model of extraintestinal growth, and that this ability provides a competitive advantage in vivo over strains lacking the don locus.

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“…1 B and C). Temporary residence within phagocytes is, incidentally, thought to be partly responsible for the refractoriness to antibiotics of staphylococci in an abscess (36,37). Metabolic shutdown would presumably contribute importantly to this refractoriness.…”

Section: Development and In Vivo Testing Of The Luciferase Reporter Smentioning

confidence: 99%

Transient interference with staphylococcal quorum sensing blocks abscess formation

Wright

Jin

Novick

2005

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

239

233

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The staphylococcal virulon is controlled largely by the agr locus, a global accessory gene regulator that is autoinduced by a self-coded peptide (AIP) and is therefore a quorum sensor. The agr locus has diverged within and between species, giving rise to AIP variants that inhibit heterologous agr activation, an effect with therapeutic potential against Staphylococcus aureus: a single dose of an inhibitory AIP blocks the formation of an experimental murine abscess. As the AIP is unstable at physiological pH, owing to its essential thiolactone bond, its single-dose efficacy seems paradoxical, which has led us to analyze the in vivo kinetics of agr activation and the consequences of its blockage by a heterologous AIP. Initially, the infecting bacteria grow rapidly, achieving sufficient population density within the first 3 h to activate agr, and then enter a neutrophil-induced metabolic eclipse lasting for 2-3 d, followed by agr reactivation concomitantly with the development of the abscess. The inhibitory AIP prevents agr expression only during its short in vivo lifetime, suggesting that the agr-induced and therefore quorum-dependent synthesis of virulence factors shortly after infection is necessary for the subsequent development of the abscess lesion and bacterial survival. We confirm this finding by showing that a sterile agr ؉ supernatant causes a sterile abscess similar to the septic abscess caused by live bacteria. These results may provide a biological rationale for regulation of virulence factor expression by quorum sensing rather than by response to specific host signals.bioluminescent imaging ͉ in vivo gene expression ͉ bacterial pathogenesis A lthough there is a large body of information on the in vitro regulation of bacterial accessory genes involved in pathogenesis (referred to here as the virulon), the in vitro environment is highly artificial and applies only imperfectly, at best, to the real-life situation. To date, however, most in vivo approaches have generated single-point transcription profiles for infecting organisms but only a handful have addressed the expression pattern of virulence determinants through time, a critical feature of any infection (1 Agr is a complex locus that controls expression of a substantial part of the staphylococcal virulon (3, 4) consistent with its central role in pathogenesis (5-8). It consists of two divergent transcription units, driven by promoters P2 and P3 (9). The P2 operon contains four genes, agrB, agrD, agrC, and agrA, all of which are required for transcriptional activation of the agr system. AgrC is the receptor and AgrA the response regulator of a two-component signal transduction module that is autoinduced by a posttranslationally modified small peptide (AIP) (10, 11), processed by AgrB from the 46-residue agrD propeptide (12). The primary function of this four-gene unit is to activate the two major agr promoters, P2 and P3, significantly aided by a second regulatory protein, SarA (13, 14). The actual effector of agrdependent exoprotein gene regulation,...

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Effects of Neutrophils on Cefazolin Activity and Penicillin-Binding Proteins in Staphylococcus aureus Abscesses

Cited by 20 publications

References 19 publications

Dps and DpsL Mediate SurvivalIn VitroandIn Vivoduring the Prolonged Oxidative Stress Response in Bacteroides fragilis

Dps and DpsL Mediate SurvivalIn VitroandIn Vivoduring the Prolonged Oxidative Stress Response in Bacteroides fragilis

Efficient utilization of complex N-linked glycans is a selective advantage for Bacteroides fragilis in extraintestinal infections

Transient interference with staphylococcal quorum sensing blocks abscess formation

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