The transcriptional regulator ArcR represses virulence and γ-hemolysin expression in Staphylococcus aureus USA300 LAC.

Abstract

Staphylococcus aureus is a major opportunistic pathogen responsible for a wide range of infections, and its pathogenicity is tightly controlled by regulatory networks linking metabolism and virulence. ArcR, a member of the Crp/Fnr family that regulates the arginine deiminase (ADI) pathway, has an unclear role in coordinating metabolism with virulence. In this study, we investigated the function of ArcR in the clinically relevant USA300 LAC strain. Deletion of arcR significantly enhanced hemolytic activity and altered the expression of toxin-associated genes, with upregulation of hla, hld, and psmα, downregulation of psmβ, and increased transcription of components of the Agr quorum-sensing system and the effector RNAIII. Mechanistically, ArcR directly repressed hlgC transcription, as demonstrated by promoter activity analysis and DNA-protein interaction assays, indicating a direct regulatory role in controlling γ-hemolysin expression. In a murine subcutaneous abscess model, the ΔarcR mutant exhibited increased virulence, characterized by larger abscesses, higher bacterial loads, and more severe tissue damage, whereas deletion of hlgC attenuated these phenotypes. In addition, disruption of ArcR altered host inflammatory responses, suggesting a role in modulating host-pathogen interactions. Collectively, these findings identify ArcR as a negative regulator of toxin production and virulence that links metabolic adaptation to toxin expression in S. aureus, at least in part through direct repression of hlgC. This study provides new insight into the regulatory mechanisms underlying staphylococcal pathogenesis and highlights ArcR as a potential target for anti-virulence strategies.