OseR, a bacterial redox sensor, regulates ergothioneine uptake via a Cys thiol switch, enhancing oxidative stress resistance and virulence

Ergothioneine (ET), a low-molecular-weight (LMW) thiol, serves as a potent antioxidant. While only a limited number of Actinomycetes and fungi can synthesize ET, most microorganisms acquire it from external sources. Recently, a microbial ET transporter system (EtUV) was identified in Helicobacter pylori and Streptococcus pneumoniae, but the regulatory mechanisms controlling EtUV in bacteria remain unknown. In this study, we identified and characterized OseR, a novel MarR family repressor in Streptococcus suis, a significant pathogen causing systemic diseases such as septicemia and meningitis in pigs and humans. We demonstrated that OseR senses oxidative stress through a thiol switch at Cys35, which regulates the ET transport system EtUV. Under oxidative stress, OseR dissociates from the promoter region of the ET transport operon due to the formation of an intermolecular disulfide bond, leading to the activation of EtUV expression. Our findings reveal that OseR not only controls ET transport but also modulates other LMW thiol transport pathways, including glutathione and cysteine, as well as genes involved in oxidative stress responses. Deletion or mutation of oseR significantly impairs oxidative stress tolerance, survival in mouse macrophages, and virulence in mice. Similarly, deletion or mutation of etU, which encodes a transmembrane permease essential for ET uptake, markedly reduces oxidative stress tolerance and virulence in mice. Importantly, our results suggest that OseR-mediated regulation of the ET transport system, driven by a thiol-based switch, may be conserved across bacterial species, highlighting a broader role for OseR in bacterial adaptation to host environments. This study advances our understanding of the regulatory mechanisms governing ET uptake in bacteria and provides new insights into the link between ET and bacterial pathogenicity.