Inactivation of the Response Regulator AgrA Has a Pleiotropic Effect on Biofilm Formation, Pathogenesis and Stress Response in Staphylococcus lugdunensis

Staphylococcus lugdunensis is a coagulase-negative Staphylococcus that emerges as an important opportunistic pathogen. However, little is known about the regulation underlying the transition from commensal to virulent state. Based on knowledge of S. aureus virulence, we suspected that the quorum sensing system may be an important determinant for the pathogenicity of . We investigated the functions of the transcriptional regulator AgrA using the deletion mutant. AgrA played a role in cell pigmentation: Δ mutant colonies were white while the parental strains were slightly yellow. Compared with the wild-type strain, the Δ mutant was affected in its ability to form biofilm and was less able to survive in mice macrophages. Moreover, the growth of Δ was significantly reduced by the addition of 10% NaCl or 0.4 mM H O and its survival after 2 h in the presence of 1 mM H O was more than 10-fold reduced. To explore the mechanisms involved beyond these phenotypes, the Δ proteome and transcriptome were characterized by mass spectrometry and RNA-Seq. We found that AgrA controlled several virulence factors as well as stress-response factors, which are well correlated with the reduced resistance of the Δ mutant to osmotic and oxidative stresses. These results were not the consequence of the deregulation of RNAIII of the system, since no phenotype or alteration of the proteomic profile has been observed for the ΔRNAIII mutant. Altogether, our results highlighted that the AgrA regulator of played a key role in its ability to become pathogenic. Although belonging to the natural human skin flora, Staphylococcus lugdunensis is recognized as a particularly aggressive and destructive pathogen. This study aimed to characterize the role of the response regulator AgrA, which is a component of the quorum-sensing system and known to be a major element in the regulation of pathogenicity and biofilm formation in Staphylococcus aureus. In the present study, we showed that, contrary to S. aureus, the deletion mutant produced less biofilm. Inactivation of conferred a white colony phenotype and impacted in its ability to survive in mice macrophages and to cope with osmotic and oxidative stresses. By global proteomic and transcriptomic approaches, we identified the AgrA regulon, bringing molecular bases underlying the observed phenotypes. Together, our data showed the importance of AgrA in the opportunistic pathogenic behavior of allowing it to be considered as an interesting therapeutic t