The AdcACB/AdcAII system is essential for zinc homeostasis and an important contributor of <i>Enterococcus faecalis</i> virulence
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Bacterial pathogens require a variety of micronutrients for growth, including trace metals such as iron, manganese, and zinc (Zn). Despite their relative abundance in host environments, access to these metals is severely restricted during infection due to host-mediated defense mechanisms collectively known as nutritional immunity. Despite a growing appreciation of the importance of Zn in host-pathogen interactions, the mechanisms of Zn homeostasis and the significance of Zn to the pathophysiology of <i>E. faecalis</i>, a major pathogen of nosocomial and community-associated infections, have not been thoroughly investigated. Here, we show that <i>E. faecalis</i> encoded ABC-type transporter AdcACB and an orphan substrate-binding lipoprotein AdcAII that work cooperatively to maintain Zn homeostasis. Simultaneous inactivation of <i>adcA</i> and <i>adcAII</i> or the entire <i>adcACB</i> operon led to a significant reduction in intracellular Zn under Zn-restricted conditions and heightened sensitivity to Zn-chelating agents including human calprotectin, aberrant cell morphology, and impaired fitness in serum <i>ex vivo</i>. Additionally, inactivation of <i>adcACB</i> and <i>adcAII</i> significantly reduced bacterial tolerance toward cell envelope-targeting antibiotics. Finally, we showed that the AdcACB/AdcAII system contributes to <i>E. faecalis</i> virulence in a <i>Galleria mellonella</i> invertebrate infection model and in two catheter-associated mouse infection models that recapitulate many of the host conditions associated with enterococcal human infections. Collectively, this report reveals that high-affinity Zn import is important for the pathogenesis of <i>E. faecalis</i> establishing the surface-associated AdcA and AdcAII lipoproteins as potential therapeutic targets.
细菌病原菌生长需要多种微量营养物质，包括铁、锰、锌（Zn）等痕量金属。尽管这些金属在宿主环境中相对充足，但在感染过程中，宿主介导的被统称为营养免疫（nutritional immunity）的防御机制会严重限制病原菌对这些金属的获取。尽管学界对锌在宿主-病原菌互作中的重要性认知不断加深，但锌稳态（Zn homeostasis）的调控机制，以及锌对于医院获得性与社区获得性感染的主要病原菌——粪肠球菌（*E. faecalis*）病理生理学的意义，尚未得到充分研究。本研究证实，粪肠球菌编码的ABC型转运体（ABC-type transporter）AdcACB与孤儿型底物结合脂蛋白AdcAII可协同维持锌稳态。同时失活adcA与adcAII基因，或是整个adcACB操纵子（operon），会在锌限制条件下显著降低细胞内锌含量，使细菌对包括人类钙卫蛋白（human calprotectin）在内的锌螯合剂敏感性升高，引发异常细胞形态，并损害其在离体血清中的生存能力。此外，失活adcACB与adcAII会显著降低细菌对靶向细胞包膜抗生素的耐受性。最后，本研究证实，AdcACB/AdcAII系统在大蜡螟（*Galleria mellonella*）无脊椎动物感染模型，以及两种可模拟人类肠球菌感染相关诸多宿主环境的导管相关性小鼠感染模型中，均可促进粪肠球菌的毒力。综上，本研究揭示了高亲和性锌摄入对粪肠球菌致病过程的重要性，并将表面定位的Adc与AdcAII脂蛋白确立为潜在治疗靶点。
