LOSS OF AGR QUORUM SENSING AND VIRULENCE FUNCTION LEADS TO EARLY GROWTH ADVANTAGE IN STAPHYLOCOCCUS AUREUS INFECTION
Alex Winnett1, Jon Femling2.
1University of Massachusetts Boston, Boston, MA, 2University of New Mexico School of Medicine, Albuquerque, NM.
Staphylococcus aureus infections present frequently to the emergency department and regularly cause significant tissue damage and systemic bacteremia. Between resistance to most available antibiotics and the failure of all anti-virulence vaccine trials to date, novel therapies are crucial to successfully combat this infection. Previous studies show that accessory gene regulation (agr) quorum sensing is an important virulence regulation pathway that mediates hundreds of genes enhancing infectivity and exacerbating disease. However, natural agr-deletion mutants (Δagr) have been isolated from hospitalized patients, suggesting that the loss of agr may have a selection advantage in some situations. We hypothesize that agr mutants will have a competitive growth advantage in immunocompromised patients compared to agr-competent strains. We have measured competitive growth of each strain following neutrophil exposure by comparing survival of Δagr versus wild-type strains in normal or antimicrobial-defense inhibited neutrophils. In addition, the effect of pharmacological inhibition (via Savirin) of the agr system on strain viability has been analyzed. We have confirmed the defect in neutrophil lysis by Δagr strains and show that there is a small decrease in bacterial killing within the first 30 minutes. After this, the kinetics of bacterial viability are similar. Using Savirin in abscess fluids taken from patients infected with S. aureus, we have identified an initial increase in bacterial viability followed by a decrease in surviving bacteria. This suggests that the regulation of bacterial virulence by agr quorum sensing has a more complex effect on bacterial survival of host immune system defenses than previously thought.