Intracellular persistence of Staphylococcus aureus : from observations to mechanisms

Staphylococcus aureus is an etiological agent involved in a multitude of infectious diseases, ranging from minor skin infections to more serious diseases. Bacterial persisters are subpopulations that adopt a transient phenotype characterized by a non-growing state and a tolerance to lethal concentrations of antibiotics. When the antibiotic treatment is discontinued, persisters give rise to a population that is, again, mostly drug susceptible. Their rare and transient nature has long hampered their experimental study, but there is now rising evidence on their implication in relapses of chronic infections. A switch to a persister phenotype has been suggested to occur inside eukaryotic cells for only very few intracellular bacteria, and the mechanisms leading to their formation are still poorly understood. Given the capacity of S. aureus to promote persistent or recurrent infections, we demonstrated that antibiotics could induce persisters within host cells and thus explain the impossibility of eradicating intracellular reservoirs. Our data further indicate that permissive host cells can host alternatively persistent bacterial forms upon antibiotic exposure, and replicative forms upon antibiotic removal and could therefore constitute a viable reservoir and a source of dissemination. Further transcriptomic analysis contributed to a better understanding of the mechanism of persistence formation. Persisters remained metabolically active and redirect energy-consuming processes to the benefit of multiple stress responses that contribute to the maintenance of vital processes, notably cell wall, DNA and transcription. In non-permissive cells, host cell oxidative stress modulates dormancy of S. aureus persisters, which may then reach different levels of dormancy but remain infectious, unveiling complex strategies developed by S. aureus to cope with the host and antibiotic treatments.