Cross-Talk between Staphylococcus aureus and Other Staphylococcal Species via the agr Quorum Sensing System

Abstract

Staphylococci are associated with both humans and animals. While most are non-pathogenic colonizers, <i>Staphylococcus aureus</i> is an opportunistic pathogen capable of causing severe infections. <i>S. aureus</i> virulence is controlled by the <i>agr</i> quorum sensing system responding to secreted auto-inducing peptides (AIPs) sensed by AgrC, a two component histidine kinase. <i>agr</i> loci are found also in other staphylococcal species and for <i>Staphylococcus epidermidis</i>, the encoded AIP represses expression of <i>agr</i> regulated virulence genes in <i>S. aureus</i>. In this study we aimed to better understand the interaction between staphylococci and <i>S. aureus</i>, and show that this interaction may eventually lead to the identification of new anti-virulence candidates to target <i>S. aureus</i> infections. Here we show that culture supernatants of 37 out of 52 staphylococcal isolates representing 17 different species inhibit <i>S. aureus agr</i>. The dog pathogen, <i>Staphylococcus schleiferi</i>, expressed the most potent inhibitory activity and was active against all four <i>agr</i> classes found in <i>S. aureus</i>. By employing a <i>S. aureus</i> strain encoding a constitutively active AIP receptor we show that the activity is mediated via <i>agr</i>. Subsequent cloning and heterologous expression of the <i>S. schleiferi</i> AIP in <i>S. aureus</i> demonstrated that this molecule was likely responsible for the inhibitory activity, and further proof was provided when pure synthetic <i>S. schleiferi</i> AIP was able to completely abolish <i>agr</i> induction of an <i>S. aureus</i> reporter strain. To assess impact on <i>S. aureus</i> virulence, we co-inoculated <i>S. aureus</i> and <i>S. schleiferi in vivo</i> in the <i>Galleria mellonella</i> wax moth larva, and found that expression of key <i>S. aureus</i> virulence factors was abrogated. Our data show that the <i>S. aureus agr</i> locus is highly responsive to other staphylococcal species suggesting that <i>agr</i> is an inter-species communication system. Based on these results we speculate that interactions between <i>S. aureus</i> and other colonizing staphylococci will significantly influence the ability of <i>S. aureus</i> to cause infection, and we propose that other staphylococci are potential sources of compounds that can be applied as anti-virulence therapy for combating <i>S. aureus</i> infections.