Abstract
Staphylococcus aureus is a Gram-positive opportunistic pathogen that imposes a heavy burden on society. What sets this pathogen apart is the sheer spectrum of infections it can cause, which range from benign skin and soft tissue infections to lethal endocarditis and bacteraemia. The ability of S. aureus to cause this gamut of infections is conferred by its arsenal of virulence factors that are under the control of the Accessory Gene Regulator (Agr) system. However, a large proportion of clinical isolates have inactivating mutations in this important regulatory system. We previously showed that, contrary to the common dogma, not all these mutations are evolutionary ‘dead-ends’ and a fraction are phase variants which can revert to an Agr active state. Here we report that some Agr deficient isolates can revert a haemolytic phenotype without repairing their Agr system. We collected as series of 30 Agr negative primary patient samples in order to assess the significance of our previous findings on the existence of Agr phase variants. We used primary samples to avoid strains that had undergone multiple clonal expansions before being tested for reversibility. We assessed Agr reversibility by serially passaging strains and screening for phenotypic reversion of haemolysis. We show that two strains reverted haemolysis and one reverted alpha haemolysin activity without any genetic changes in agr (and hla for the alpha revertant). These results add further complexity to the phenomenon of Agr shutdown observed in the clinical setting and corroborate recent findings of compensatory mutations arising in Agr deficient clinical strains.
Highlights
Staphylococcus aureus is a clinically important opportunistic pathogen that merits attention due to the diversity and severity of infections that it causes [1]
Samples are streaked towards a β-haemolysin producing strain and if the sample produces δ-haemolysin, a direct indicator of Accessory Gene Regulator (Agr) activation, an arrowhead pattern of haemolysis emerges from the synergistic effect of β and δ haemolysins
Alpha haemolysin is inhibited by β-haemolysin, if the samples produces α-haemolysin an inhibition of haemolysis at the convergence of the two streaks is observed
Summary
Staphylococcus aureus is a clinically important opportunistic pathogen that merits attention due to the diversity and severity of infections that it causes [1]. The responsibility for providing this balance falls to the global virulence regulatory system, the Accessory Gene Regulator (Agr) system. The Agr system consists of two divergently transcribed loci that encode for a quorum sensing circuit and a regulatory RNA gene [3]. Cells produce a basal level of an autoinducing pheromone encoded in the quorum sensing circuit and when the extracellular concentration of this pheromone surpasses a threshold the cell detects it and transcribes the regulatory RNA, RNAIII, in response. RNAIII de-represses the translation of Staphylococcus aureus
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