Master transcriptional regulator SaeS in <i>Staphylococcus aureus</i> contributes to staphyloxanthin biosynthesis to promote survival during invasive infection

Staphylococcus aureus is a major human opportunistic pathogen that causes significant morbidity and mortality, particularly in immunocompromised individuals. SaeRS is a two-component system in S. aureus that regulates signal transduction related to virulence, including hemolysis and coagulation. Metal ions are essential nutrients that support bacterial virulence and survival against host immune cells and are intricately interconnected with regulatory systems. The SaeRS system has long been studied for its function in bacterial virulence and invasive infections. However, its interactions with other regulators and metal ions remain unelucidated. Thus, this study evaluated the effects of the S. aureus SaeRS system on virulence, specifically its association with oxidative stress resistance and staphyloxanthin (STX) production. saeS deletion reduced STX production via the SigB-CrtOPQMN pathway, increasing vulnerability to oxidative stress and susceptibility to host immune cells. Supplementation with metal ions, specifically zinc, inhibited STX-associated gene expression, attenuating antioxidative activity in vitro. Experiments on mice with S. aureus bloodstream infection verified that SaeS was crucial for bacterial survival in vivo. Furthermore, zinc contributed to weakened bacterial virulence and altered host immune defense mechanisms. Collectively, our results established a novel mechanistic interconnection between SaeRS and STX biosynthesis and demonstrated that SaeRS inhibition combined with zinc supplementation promotes innate immune system-mediated killing of S. aureus.金黄色葡萄球菌（Staphylococcus aureus）是人类主要的机会致病菌，可引发严重的发病率与死亡率，在免疫功能低下人群中尤为显著。SaeRS是金黄色葡萄球菌中的双组分系统（two-component system），可调控与毒力相关的信号转导过程，包括溶血作用与凝固作用。金属离子是维持细菌毒力、帮助细菌抵御宿主免疫细胞的必需营养素，且与细菌的调控系统存在紧密的相互关联。长期以来，学界围绕SaeRS系统在细菌毒力与侵袭性感染中的功能开展了诸多研究，但其与其他调控因子及金属离子的相互作用仍未得到阐明。因此本研究评估了金黄色葡萄球菌SaeRS系统对细菌毒力的影响，重点探讨其与抗氧化应激能力及金黄色葡萄球菌黄素（staphyloxanthin，STX）合成的关联。saeS基因缺失通过SigB-CrtOPQMN通路降低了STX的合成，增强了细菌对氧化应激的易感性，同时提升了其对宿主免疫细胞杀伤的敏感性。补充金属离子（尤其是锌）可抑制STX相关基因的表达，在体外减弱细菌的抗氧化活性。针对金黄色葡萄球菌血流感染小鼠的动物实验证实，SaeS对细菌在体内的存活至关重要。此外，锌可削弱细菌的毒力，并改变宿主的免疫防御机制。综上，本研究结果揭示了SaeRS与STX生物合成之间全新的机制性关联，并证实联合抑制SaeRS与补充锌可促进固有免疫系统（innate immune system）对金黄色葡萄球菌的杀伤作用。