Phenotypic heterogeneity and temporal expression of the capsular polysaccharide inStaphylococcus aureus

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Bacteria respond to ever-changing environments through several adaptive strategies. This includes mechanisms leading to a high degree of phenotypic variability within a genetically homogeneous population. InStaphylococcus aureus, the capsular polysaccharide (CP) protects against phagocytosis, but also impedes adherence to endothelial cells and/or matrix proteins. We analysed the regulation of core biosynthesis genes (capA-P) necessary for CP synthesis using single-cell assays (immunofluorescence and promoter-activity). In persistent human carriers, we found a distinct subpopulation of nasalS. aureusto be CP positive.In vitro,capexpression is also heterogeneous and strongly growth-phase dependent. We asked whether this peculiar expression pattern (earlyOff/lateHeterogen) is orchestrated by the quorum system Agr. We show that the Agr-driven effector molecule RNAIII promotescapexpression largely via inactivation of the repressor Rot. High NaCl, deletion of CodY or Sae also resulted in highercapexpression but did not change the earlyOFF/lateHeterogen expression pattern. Activity of the quorum system itself is largely homogenous and does not account for the observed heterogeneity ofcapexpression or the strictly growth phase dependent expression. Our findings are in contrast to the prevailing view that quorum sensing is the main driving force for virulence gene expression when bacterial cell densities increase.

During exponential growth, cap genes involved in capsular polysaccharide biosynthesis are tightly repressed. In the later growth phase, the repressor Rot is inactivated via quorum sensing and CodY through limitation of ligands; GTP and/or branched chain amino acids. However, cap repression is only partially relieved, leaving a distinct sub-population un-encapsulated. Heterogeneous cap expression also occurs during human nasal colonization. Such bistability may have evolved to avoid phagocytosis (encapsulated bacteria) while simultaneously allowing adherence (non-encapsulated bacteria).

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