XerC Contributes to Diverse Forms of Staphylococcus aureus Infection via agr -Dependent and agr -Independent Pathways

Abstract

We demonstrate that mutation of xerC, which reportedly encodes a homologue of an Escherichia coli recombinase, limits biofilm formation in the methicillin-resistant Staphylococcus aureus strain LAC and the methicillin-sensitive strain UAMS-1. This was not due to the decreased production of the polysaccharide intracellular adhesin (PIA) in either strain because the amount of PIA was increased in a UAMS-1 xerC mutant and undetectable in both LAC and its isogenic xerC mutant. Mutation of xerC also resulted in the increased production of extracellular proteases and nucleases in both LAC and UAMS-1, and limiting the production of either class of enzymes increased biofilm formation in the isogenic xerC mutants. More importantly, the limited capacity to form a biofilm was correlated with increased antibiotic susceptibility in both strains in the context of an established biofilm in vivo. Mutation of xerC also attenuated virulence in a murine bacteremia model, as assessed on the basis of the bacterial loads in internal organs and overall lethality. It also resulted in the decreased accumulation of alpha toxin and the increased accumulation of protein A. These findings suggest that xerC may impact the functional status of agr. This was confirmed by demonstrating the reduced accumulation of RNAIII and AgrA in LAC and UAMS-1 xerC mutants. However, this cannot account for the biofilmdeficient phenotype of xerC mutants because mutation of agr did not limit biofilm formation in either strain. These results demonstrate that xerC contributes to biofilm-associated infections and acute bacteremia and that this is likely due to agr-independent and -dependent pathways, respectively. Staphylococcus aureus is a ubiquitous human pathogen capable of causing a wide variety of infections. These range from acute infections like bacteremia to chronic biofilm-associated infections. It is generally assumed that severe, acute infections are defined by the production of extracellular toxins, but a recent report demonstrated a negative correlation between toxicity for mammalian cells and invasive disease among human isolates (1). Although expression of the accessory gene regulator (agr), which is a primary determinant of toxin production (2), is negatively correlated with biofilm formation (3, 4), no correlation between toxicity and biofilm formation was observed in the current study. In fact, the only correlation was that decreased toxicity was associated with increased fitness, as assessed on the basis of survival in human serum (1).Nevertheless, it is clear that S. aureus has the capacity to cause diverse forms of infection. In the case of acute infections, the primary therapeutic concern is acquired resistance and the decreasing availability of effective antibiotics (5). In the case of biofilmassociated infections, a critical concern is the biofilm itself, which confers a therapeutically relevant level of intrinsic resistance to both host defenses and conventional antibiotics (6-9). There are multiple reasons for this, including the limited...

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