Cooperation, Quorum Sensing, and Evolution of Virulence in Staphylococcus aureus

The virulence and fitness in vivo of the major human pathogen Staphylococcus aureus are associated with a cell-to-cell signaling mechanism known as quorum sensing (QS). QS coordinates the production of virulence factors via the production and sensing of autoinducing peptide (AIP) signal molecules by the agr locus. Here we show, in a waxmoth larva virulence model, that (i) QS in S. aureus is a cooperative social trait that provides a benefit to the local population of cells, (ii) agrmutants, which do not pro-duce or respond to QS signal, are able to exploit the benefits provided by the QS of others (“cheat”), allowing them to increase in frequency when in mixed populations with cooperators, (iii) these social interactions between cells determine virulence, with the host mortality rate being negatively correlated to the percentage of agrmutants (“cheats”) in a population, and (iv) a higher within-host relatedness (lower strain diversity) selects for QS and hence higher virulence. Our results provide an explanation for why agrmutants show reduced virulence in animal models but can be isolated from infections of humans. More generally, by providing the first evidence that QS is a cooperative social behavior in a Gram-positive bacterium, our results suggest conver-gent, and potentially widespread, evolution for signaling to coordinate cooperation in bacteria. Staphylococcus aureus is a major human pathogen, responsiblefor 1 % of all hospital admissions and leading to an estimated cost of $9.5 billion per year in the United States alone (1–4). In-fections caused by S. aureus range from relatively mild boils and infected skin wounds to those with high mortality rates, such a