Genome Plasticity of agr -Defective Staphylococcus aureus during Clinical Infection

Therapy for bacteremia caused by is often ineffective, even when treatment conditions are optimal according to experimental protocols. Adapted subclones, such as those bearing mutations that attenuate -mediated virulence activation, are associated with persistent infection and patient mortality. To identify additional alterations in -defective mutants, we sequenced and assembled the complete genomes of clone pairs from colonizing and infected sites of several patients in whom demonstrated a within-host loss of function. We report that events associated with inactivation result in -defective blood and nares strain pairs that are enriched in mutations compared to pairs from wild-type controls. The random distribution of mutations between colonizing and infecting strains from the same patient, and between strains from different patients, suggests that much of the genetic complexity of -defective strains results from prolonged infection or therapy-induced stress. However, in one of the -defective infecting strains, multiple genetic changes resulted in increased virulence in a murine model of bloodstream infection, bypassing the mutation of and raising the possibility that some changes were selected. Expression profiling correlated the elevated virulence of this -defective mutant to restored expression of the -regulated ESAT6-like type VII secretion system, a known virulence factor. Thus, additional mutations outside the locus can contribute to diversification and adaptation during infection by mutants associated with poor patient outcomes.