The global regulator SpoVG modulates <i>Staphylococcus aureus</i> virulence through Agr-dependent pathways

<i>Staphylococcus aureus</i> (<i>S. aureus</i>) is a major pathogen responsible for a wide range of infections in both community and healthcare settings. Its virulence is orchestrated by a complex regulatory network. SpoVG, a global regulator in <i>S. aureus</i>, has been shown to play crucial roles in antibiotic tolerance, stress adaptation, and biofilm formation. However, its specific role in virulence regulation has remained poorly understood. Here, we investigated the role of SpoVG in the modulation of <i>S. aureus</i> virulence. The results demonstrate that deletion of <i>spoVG</i> significantly increased the hemolytic activity and virulence of the SA3 strain, as evidenced by both in vitro assays and murine infection models. Transcriptomic profiling and RT – qPCR analyses revealed that the inactivation of <i>spoVG</i> activated the Agr quorum-sensing system, resulting in upregulating key virulence genes, including <i>psmα</i>, <i>psmβ</i>, <i>hla</i>, and <i>hlg</i>. Further, β-galactosidase reporter assays and electrophoretic mobility shift assays (EMSA) confirmed that SpoVG directly binds to the promoter regions of <i>agrACDB</i>, <i>psmα</i>, and <i>psmβ</i>, thereby repressing their transcription. Collectively, these findings identify SpoVG as a critical negative regulator of virulence in <i>S. aureus</i>, acting through direct repression of the Agr system and its downstream effectors. This study provides new mechanistic insights into SpoVG-mediated virulence regulation and highlights SpoVG as a potential target for anti-virulence strategies against <i>S. aureus</i> infections.