Transient Interference with Staphylococcal Quorum Sensing Blocks Abscess Formation

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 ac...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2005-02, Vol.102 (5), p.1691-1696
Main Authors: Wright, Jesse S., Jin, Rhuzong, Novick, Richard P., Falkow, Stanley
Format: Article
Language:English
Subjects:
Abscess - microbiology
Abscess - pathology
Abscesses
Animals
Bacteria
Bacterial Proteins - metabolism
Biological Sciences
Disease Models, Animal
Dosage
Eclipses
Genetics
Infections
Lesions
Metabolism
Mice
Mice, Hairless
Microbiology
Peptides
Plasmids
Signal transduction
Staphylococcus
Staphylococcus - genetics
Staphylococcus - pathogenicity
Staphylococcus aureus
Virulence
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0407661102