The alternative sigma factor sigma B of Staphylococcus aureus modulates virulence in experimental central venous catheter-related infections

Lorenz, Udo; Hüttinger, Christian; Schäfer, Tina; Ziebuhr, Wilma; Thiede, A.; Hacker, Jörg; Engelmann, Susanne; Hecker, Michael; Ohlsen, Knut

doi:10.1016/j.micinf.2007.11.006

Cited by 33 publications

(25 citation statements)

References 32 publications

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“…The sigB mutants were selected with erythromycin and further confirmed by diagnostic PCR and DNA sequencing. The donor sigB allelic-replacement mutant was kindly provided by Knut Ohlsen (43).…”

Section: Methodsmentioning

confidence: 99%

The Staphylococcus aureus AirSR Two-Component System Mediates Reactive Oxygen Species Resistance via Transcriptional Regulation of Staphyloxanthin Production

et al. 2017

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Staphylococcus aureus is an important opportunistic pathogen and is the etiological agent of many hospital-and community-acquired infections. The golden pigment, staphyloxanthin, of S. aureus colonies distinguishes it from other staphylococci and related Gram-positive cocci. Staphyloxanthin is the product of a series of biosynthetic steps that produce a unique membrane-embedded C 30 golden carotenoid and is an important antioxidant. We observed that a strain with an inducible airR overexpression cassette had noticeably increased staphyloxanthin production compared to the wild-type strain under aerobic culturing conditions. Further analysis revealed that depletion or overproduction of the AirR response regulator resulted in a corresponding decrease or increase in staphyloxanthin production and susceptibility to killing by hydrogen peroxide, respectively. Furthermore, the genetic elimination of staphyloxanthin during AirR overproduction abolished the protective phenotype of increased staphyloxanthin production in a whole-blood survival assay. Promoter reporter and gel shift assays determined that the AirR response regulator is a direct positive regulator of the staphyloxanthin-biosynthetic operon, crtOPQMN, but is epistatic to alternative sigma factor B. Taken together, these data indicate that AirSR positively regulates the staphyloxanthin-biosynthetic operon crtOPQMN, promoting survival of S. aureus in the presence of oxidants.KEYWORDS: S. aureus, staphyloxanthin, transcriptional regulation, AirSR, twocomponent regulatory systems S taphylococcus aureus is a leading bacterial agent of hospital-and communityacquired infections ranging from infective endocarditis and osteomyelitis to soft tissue infection (1). S. aureus possesses a vast array of adhesion and virulence factors that allow the organism to infect any part of the body and efficiently evade the immune system. S. aureus colonies are orange to golden (hence the species name, aureus), which was previously used as a distinguishing characteristic and is now recognized as the product of an important virulence factor (2).The distinctive golden pigment of S. aureus is the biosynthetic product of crtOPQMN and aldH (3, 4). The final product of this six-enzyme-biosynthetic pathway is a membrane-embedded golden C 30 triterpenoid carotenoid, ␣-D-glucopyranosyl-1-O-(4,4=-diaponeurosporen-4-oate)-6-O-(12-methyltetradecanoate), termed staphyloxanthin (STX) (5). STX is an antioxidant (6) and an important virulence factor of S. aureus, promoting intracellular phagocyte survival, and is linked to resistance to reactive oxygen species (ROS) produced by the NADPH oxidase system within the phagocyte phagosome (2).

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Section: Methodsmentioning

confidence: 99%

The Staphylococcus aureus AirSR Two-Component System Mediates Reactive Oxygen Species Resistance via Transcriptional Regulation of Staphyloxanthin Production

et al. 2017

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“…Age-, gender-, and weight-matched NMRI mice (Charles River, Sulzfeld, Germany) were used in the experiment. Mice were intraperitoneally anesthetized with xylazine (8 mg/kg body weight) and ketamine (100 mg/kg body weight), and a central venous catheter was surgically placed as already described (23). Twenty-four hours after surgery, the mice were inoculated via the catheter with 100 l of an S. aureus suspension containing 1 ϫ 10 7 CFU S. aureus bacteria.…”

Section: Methodsmentioning

confidence: 99%

“…We recently developed an animal model of S. aureus catheter-induced sepsis in immunocompetent mice that closely mimics the clinicopathological features of human disease (23). By application of this experimental system and a sepsis survival model in mice, the immunotherapeutic potential of a murine monoclonal antibody (MAb) recognizing IsaA was investigated.…”

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confidence: 99%

Functional Antibodies Targeting IsaA of Staphylococcus aureus Augment Host Immune Response and Open New Perspectives for Antibacterial Therapy

Lorenz¹,

Lorenz

Schmitter

et al. 2011

Antimicrob Agents Chemother

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Staphylococcus aureusis the most common cause of nosocomial infections. Multiple antibiotic resistance and severe clinical outcomes provide a strong rationale for development of immunoglobulin-based strategies. Traditionally, novel immunological approaches against bacterial pathogens involve antibodies directed against cell surface-exposed virulence-associated epitopes or toxins. In this study, we generated a monoclonal antibody targeting the housekeeping protein IsaA, a suggested soluble lytic transglycosylase ofS. aureus, and tested its therapeutic efficacy in two experimental mouse infection models. A murine anti-IsaA antibody of the IgG1 subclass (UK-66P) showed the highest binding affinity in Biacore analysis. This antibody recognized allS. aureusstrains tested, including hospital-acquired and community-acquired methicillin-resistantS. aureusstrains. Therapeutic efficacyin vivoin mice was analyzed using a central venous catheter-related infection model and a sepsis survival model. In both models, anti-IsaA IgG1 conferred protection against staphylococcal infection.Ex vivo, UK-66P activates professional phagocytes and induces highly microbicidal reactive oxygen metabolites in a dose-dependent manner, resulting in bacterial killing. The study provides proof of concept that monoclonal IgG1 antibodies with high affinity to the ubiquitously expressed, single-epitope-targeting IsaA are effective in the treatment of staphylococcal infection in different mouse models. Anti-IsaA antibodies might be a useful component in an antibody-based therapeutic for prophylaxis or adjunctive treatment of human cases ofS. aureusinfections.

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“…Experiments with this infection model were performed similarly to those described in a previous study (12). Briefly, female Naval Medical Research Institute (NMRI) mice (Charles River, Sulzfeld, Germany) weighing 30 to 35 g were acclimated for 1 week prior to surgery in the animal facility.…”

Section: Methodsmentioning

confidence: 99%

“…The aims of the present study were (i) to assess the in vivo activity of a novel recombinant form of lysostaphin using a murine model of S. aureus central venous catheter-associated infection (12) and a deep tissue infection model (13) and (ii) to evaluate two in vivo imaging modalities, bioluminescence imaging (BLI) and 19 F magnetic resonance imaging (MRI) with perfluorocarbons (PFC), as markers to study the dynamics of antibiotic action during disease progression. Currently, determination of CFU after recovery of infected organs at the end of the experiment represents the gold standard in vivo preclinical testing method for the evaluation of antibacterial agents, but this procedure delivers no information on the dynamics of the infection and the hostpathogen interaction.…”

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confidence: 99%

Bioluminescence and ¹⁹ F Magnetic Resonance Imaging Visualize the Efficacy of Lysostaphin Alone and in Combination with Oxacillin against Staphylococcus aureus in Murine Thigh and Catheter-Associated Infection Models

Hertlein

Sturm

Lorenz

et al. 2014

Antimicrob Agents Chemother

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Staphylococci are the leading cause of hospital-acquired infections worldwide. Increasingly, they resist antibiotic treatment owing to the development of multiple antibiotic resistance mechanisms in most strains. Therefore, the activity and efficacy of recombinant lysostaphin as a drug against this pathogen have been evaluated. Lysostaphin exerts high levels of activity against antibiotic-resistant strains of Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). The therapeutic value of lysostaphin has been analyzed in two different clinically relevant in vivo models, a catheter-associated infection model and a thigh infection model. We infected mice with luciferase-expressing S. aureus Xen 29, and the efficacies of lysostaphin, vancomycin, oxacillin, and combined lysostaphin-oxacillin were investigated by determining numbers of CFU, detecting bioluminescent signals, and measuring the accumulation of perfluorocarbon emulsion at the site of infection by 19 F magnetic resonance imaging. Lysostaphin treatment significantly reduced the bacterial burden in infected thigh muscles and, after systemic spreading from the catheter, in inner organs. The efficiency of lysostaphin treatment was even more pronounced in combinatorial therapy with oxacillin. These results suggest that recombinant lysostaphin may have potential as an anti-S. aureus drug worthy of further clinical development. In addition, both imaging technologies demonstrated efficacy patterns similar to that of CFU determination, although they proved to be less sensitive. Nonetheless, they served as powerful tools to provide additional information about the course and gravity of infection in a noninvasive manner, possibly allowing a reduction in the number of animals needed for research evaluation of new antibiotics in future studies.

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The alternative sigma factor sigma B of Staphylococcus aureus modulates virulence in experimental central venous catheter-related infections

Cited by 33 publications

References 32 publications

The Staphylococcus aureus AirSR Two-Component System Mediates Reactive Oxygen Species Resistance via Transcriptional Regulation of Staphyloxanthin Production

The Staphylococcus aureus AirSR Two-Component System Mediates Reactive Oxygen Species Resistance via Transcriptional Regulation of Staphyloxanthin Production

Functional Antibodies Targeting IsaA of Staphylococcus aureus Augment Host Immune Response and Open New Perspectives for Antibacterial Therapy

Bioluminescence and ¹⁹ F Magnetic Resonance Imaging Visualize the Efficacy of Lysostaphin Alone and in Combination with Oxacillin against Staphylococcus aureus in Murine Thigh and Catheter-Associated Infection Models

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The alternative sigma factor sigma B of Staphylococcus aureus modulates virulence in experimental central venous catheter-related infections

Cited by 33 publications

References 32 publications

The Staphylococcus aureus AirSR Two-Component System Mediates Reactive Oxygen Species Resistance via Transcriptional Regulation of Staphyloxanthin Production

The Staphylococcus aureus AirSR Two-Component System Mediates Reactive Oxygen Species Resistance via Transcriptional Regulation of Staphyloxanthin Production

Functional Antibodies Targeting IsaA of Staphylococcus aureus Augment Host Immune Response and Open New Perspectives for Antibacterial Therapy

Bioluminescence and 19 F Magnetic Resonance Imaging Visualize the Efficacy of Lysostaphin Alone and in Combination with Oxacillin against Staphylococcus aureus in Murine Thigh and Catheter-Associated Infection Models

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Bioluminescence and ¹⁹ F Magnetic Resonance Imaging Visualize the Efficacy of Lysostaphin Alone and in Combination with Oxacillin against Staphylococcus aureus in Murine Thigh and Catheter-Associated Infection Models