Staphylococcus aureus Survival During Nutrient Restriction and Suppression of Host Immunity

 描述(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。仅在美国，每年就有30万人因金黄色葡萄球菌住院，11000人死亡，显然，为治疗这些感染而实施的临床治疗标准是不够的。这个 与目前的治疗策略相关的不良疗效部分源于感染菌株中抗生素抗药性的增加，以及获得新的毒力特征，从而促进 在不适宜居住的宿主环境中生存。此外，几个世纪以来，金黄色葡萄球菌作为皮肤和鼻腔的短暂共生体与其人类宿主一起进化。作为这种密切联系的结果，这种细菌已经变得非常好地配备了广泛和高度冗余的因子武器库，使其能够避开主要的宿主防御并促进生存。因此，金黄色葡萄球菌一旦突破其共生生态位，几乎可以在每一个宿主组织中繁衍生息。如果我们要在临床上成功对抗金黄色葡萄球菌，当务之急是 我们了解细菌用来逃避宿主防御和适应体内生长限制的各种机制。在这种情况下，我们的实验室旨在破译金黄色葡萄球菌有效地篡夺宿主先天免疫并适应营养不足从而导致疾病的新机制。这项赠款的初步数据表明，金黄色葡萄球菌对代谢物脂肪酸盐的新生物合成和回收是金黄色葡萄球菌生存的关键。 在感染过程中特定组织中的细菌。此外，我们已经确定，脂酸盐的从头生物合成通过限制巨噬细胞激活的抗炎特性促进疾病的持久性。在宿主内，生物可利用的脂酸盐很低，细菌必须 适应在长期禁食期间获得代谢物。金黄色葡萄球菌似乎使用独特的脂类生物合成和回收机制来抵消这种营养限制并促进复制。因此，我们的数据强调了两个与脂类回收/生物合成和致病机制相关的新假说：(I)金黄色葡萄球菌脂酸盐生物合成抑制先天免疫细胞活性，使其能够逃避免疫防御；(Ii)金黄色葡萄球菌的脂酸盐获取机制使细菌能够克服宿主的关键营养缺乏，从而在不同部位感染期间实现最佳适应性。这项应用的目的是：(1)确定金黄色葡萄球菌的脂类生物合成和回收途径；(2)研究含有脂类的因子如何抑制巨噬细胞的激活；以及(3)评估脂类的生物合成和回收如何有助于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.