Staphylococcus aureus Survival During Nutrient Restriction and Suppression of Host Immunity

 描述（由申请人提供）：金黄色葡萄球菌是一种在医院和社区造成重大疾病负担的细菌。每年有30万人住院治疗，11,000人死亡。金黄色葡萄球菌感染，很明显，用于治疗这些感染的临床治疗标准是不够的。的 与当前治疗策略相关的疗效差部分源于感染性分离株中抗生素耐药性的上升，以及获得新的毒力性状， 在恶劣的宿主环境中生存。此外，S.金黄色葡萄球菌作为皮肤和鼻腔的暂时寄生物与其人类宿主一起进化了几个世纪。由于这种密切的联系，细菌已经变得非常好地装备了广泛和高度冗余的因子库，使其能够逃避主要的宿主防御并促进生存。因此，S.金黄色葡萄球菌在突破其寄生小生境后几乎可以在每一个宿主组织中蓬勃发展。如果我们要成功地对抗S。金黄色葡萄球菌在临床上， 我们了解细菌逃避宿主防御和适应体内生长限制的不同机制。在这种情况下，我们的实验室的目标是破译新的机制，S。金黄色葡萄球菌有效地篡夺宿主先天免疫并适应营养缺乏以引起疾病。本研究的初步数据表明，S.金黄色葡萄球菌对 在感染过程中特定组织中的细菌此外，我们已经确定，通过限制巨噬细胞活化的抗炎特性，硫辛酸的从头生物合成促进疾病的持续性。在宿主体内，生物可利用的硫辛酸是低的，细菌必须 适应在长时间限制期间获得代谢物。S.金黄色葡萄球菌似乎使用独特的硫辛酸生物合成和补救机制来抵消这种营养限制并促进复制。因此，我们的数据突出了与硫辛酸补救/生物合成和发病机制相关的两个新假设：（i）S。金黄色葡萄球菌的硫辛酸生物合成抑制先天免疫细胞活性，从而使其逃避免疫防御;金黄色葡萄球菌使细菌能够克服宿主的严重营养缺乏，从而在不同部位的感染期间实现最佳适应性。本研究的主要目的是：（1）明确S.金黄色;（2）研究含脂肪酸的因子如何抑制巨噬细胞活化;（3）评估脂肪酸的生物合成和补救如何促进代谢适应和宿主炎症。

 DESCRIPTION (provided by applicant): Staphylococcus aureus is a bacterium that causes significant disease burden in hospitals and communities. With a yearly toll of 300,000 hospitalizations and 11,000 deaths caused by S. aureus in the United States alone, it is clear that the clinical therapeutic standards implemented to treat these infections are insufficient. The poor efficacy associated with current treatment strategies stems in part from a rise in antibiotic resistance among infectious isolates, as well as acquisition of novel virulence traits that promote survival within inhospitable host environments. In addition, S. aureus has evolved for centuries alongside its human host as a transient commensal of the skin and nasal cavity. As a consequence of this intimate association, the bacterium has become remarkably well equipped with a broad and highly redundant arsenal of factors that allow it to evade major host defenses and promote survival. Thus, S. aureus can flourish in nearly every host tissue upon breaching its commensal niche. If we are to successfully combat S. aureus in the clinic it is imperative that we understand the diverse mechanisms used by the bacterium to evade host defenses and adapt to growth restriction in vivo. In this vein, our laboratory aims to decipher novel mechanisms by which S. aureus effectively usurps host innate immunity and adapts to nutritional deficiencies in order to cause disease. The preliminary data in this grant indicate tha de novo biosynthesis and salvage of the metabolite lipoate by S. aureus is critical for survival of the bacterium in specific tissues during infection. Furthermore, we have determined that de novo biosynthesis of lipoate promotes disease persistence through anti-inflammatory properties that restrict macrophage activation. Within the host, bioavailable lipoate is low and bacteria must adapt to acquire the metabolite during periods of prolonged restriction. S. aureus appears to use unique lipoate biosynthetic and salvage mechanisms to offset this nutritional restriction and foster replication. Thus, our data highlight two novel hypotheses associated with lipoate salvage/biosynthesis and pathogenesis: (i) S. aureus lipoate biosynthesis suppresses innate immune cell activity allowing escape from immune defenses and (ii) the lipoate acquisition mechanisms of S. aureus allow the bacterium to overcome critical nutritional deficiencies in the host thereby enabling optimal fitness during infection at diverse sites. The Aims of this application are to: (1) Define the lipoate biosynthesis and salvage pathways of S. aureus; (2) Investigate how lipoate-containing factors suppress macrophage activation; and (3) Evaluate how lipoate biosynthesis and salvage contribute to metabolic adaptation and host inflammation.