Staphylococcus epidermidis agr Quorum-Sensing System: Signal Identification, Cross Talk, and Importance in Colonization

Staphylococcus epidermidis is an opportunistic pathogen that is one of the leading causes of medical device infections. Global regulators like theagr quorum-sensing system in this pathogen have received a limited amount of attention, leaving important questions unanswered. There are threeagr types inS. epidermidis strains, but only one of the autoinducing peptide (AIP) signals has been identified (AIP-I), and cross talk betweenagr systems has not been tested. We structurally characterized all three AIP types using mass spectrometry and discovered that the AIP-II and AIP-III signals are 12 residues in length, making them the largest staphylococcal AIPs identified to date.S. epidermidis agr reporter strains were developed for each system, and we determined that cross-inhibitory interactions occur between theagr type I and II systems and between theagr type I and III systems. In contrast, no cross talk was observed between the type II and III systems. To further understand the outputs of theS. epidermidis agr system, an RNAIII mutant was constructed, and microarray studies revealed that exoenzymes (Ecp protease and Geh lipase) and low-molecular-weight toxins were downregulated in the mutant. Follow-up analysis of Ecp confirmed the RNAIII is required to induce protease activity and thatagr cross talk modulates Ecp activity in a manner that mirrors theagr reporter results. Finally, we demonstrated that theagr system enhances skin colonization byS. epidermidis using a porcine model. This work expands our knowledge ofS. epidermidis agr system function and will aid future studies on cell-cell communication in this important opportunistic pathogen.