STAPHYLOCOCCUS-AUREUS AGR AND SAR GLOBAL REGULATORS INFLUENCE INTERNALIZATION AND INDUCTION OF APOPTOSIS

Staphylococcus aureus was recently shown to be internalized by and to induce apoptosis in a bovine mammary epithelial cell line, suggesting that these processes could be involved in staphylococcal pathogenesis or persistence. Tb examine the role of virulence factor regulators dur ing internalization, mutant agr and sai strains of S. aureus were anal yzed for their abilities to enter and induce apoptosis in epithelial c ells. Like a previously characterized bovine mastitis isolate, the sta ndard laboratory strain, RN6390 (wild type), entered the epithelial ce lls and subsequently induced apoptosis. In contrast, the mutant strain s RN6911 (agr), ALC136 (sar), and ALC135 (agr sar) were internalized b y the;cultured cells at levels reproducibly greater than that for RN63 90 but failed to induce apoptosis. The internalization of S. aureus wa s affected by growth phase, suggesting a role for agr-regulated surfac e proteins in this process. Furthermore, the ability to induce apoptos is required metabolically active intracellular bacteria. These data in dicate that the ability of S. aureus to enter mammalian cells and indu ce apoptosis is dependent on factors regulated by Agr and Sar. Since t ranscriptional control by these global regulators Is mediated by quoru m-sensing and environmental factors, staphylococci may have the potent ial to induce several alternative effects on Cells from an intracellul ar environment. A model for the function of the agr locus in the conte xt of internalization, intracellular persistence, and dissemination is proposed.