THE ACCESSORY GENE REGULATOR (AGR) CONTROLS STAPHYLOCOCCUS-AUREUS VIRULENCE IN A MURINE ARTHRITIS MODEL

We have studied the role of the accessory gene regulator (agr) of Stap hylococcus aureus as a virulence determinant in the pathogenesis of se ptic arthritis. At least 15 genes coding for potential virulence facto rs in Staphylococcus aureus are regulated by a putative multicomponent signal transduction system encoded by the agr/hld locus. agr and hld mutants show a decreased synthesis of extracellular toxins and enzymes , such as alpha-, beta-, and delta-hemolysin, leucocidin, lipase, hyal uronate lyase, and proteases, and at the same time an increased synthe sis of coagulase and protein A as compared with the wild-type counterp art. We have used a recently described murine model of S. aureus-induc ed arthritis to study the virulence of S. aureus 83254 and two agr/hld mutants derived from it. Sixty percent of the mice injected with the wild-type strain developed arthritis, whereas agrA and hld mutants dis played joint involvement in only 10 and 30%, respectively. In addition , 40% of the mice inoculated with the wild type strain displayed an er osive arthropathy; such changes were not detectable at all in mice ino culated with the agrA mutant. Serum levels of interleukin-6, a potent B-cell differentiation factor, were significantly higher (P < 0.001) i n the mice inoculated with the wild-type strain than in those inoculat ed with the agrA mutant counterpart. Overall, our results suggest that the agr system of S. aureus is an important virulence determinant in the induction and progression of septic arthritis in mice.