Metabolomic Mechanisms of Nutritional Immunity in the Urinary Tract

项目总结 尿路感染(UTIs)很常见，促使抗生素的广泛使用，而且越来越多 对治疗有抗药性。人们普遍认为，尿液的化学成分对 在UTI发病机制中的作用，但这一直难以转化为临床实践。最近，我们发现了很宽的 尿液中天然免疫蛋白支持抗菌铁螯合能力的个体差异 西德罗卡林(SCN；也称为Lipocalin-2或NGAL)。利用基于质谱学的代谢组学，我们 将这些差异与人类尿液代谢物的一种特定化学类别联系起来。这项工作和其他工作 支持尿液代谢产物在先天抗菌免疫中的作用。临床尿路病原菌 对泌尿环境有大量的表型和遗传适应，提示有多种选择性 与尿液成分有关的压力。在这里，我们将确定人类尿液代谢对尿路感染的影响 发病机制。由于人类尿液是一种化学复杂的生物流体，我们将结合最新的生物分析 用当代数据科学方法识别影响代谢网络的进展 细菌的生长和行为。通过识别这些网络，探索它们的精确生化功能，以及 了解它们的生理起源，我们将为转化为患者护理提供基础。建议的分析 实验对我们的假设进行了严格的评估，即尿液成分在 在抵抗感染方面发挥作用，并应在治疗上有针对性地预防或治疗感染。

PROJECT SUMMARY Urinary tract infections (UTIs) are commonplace, drive extensive antibiotic use, and are becoming increasingly resistant to treatment. There is general agreement that the chemical composition of urine plays an influential role in UTI pathogenesis but this has been difficult to translate to clinical practice. Recently, we found wide individual differences in urine's ability to support antibacterial iron chelation by the innate immune protein siderocalin (SCN; also known as Lipocalin-2 or NGAL). Using mass spectrometry-based metabolomics, we linked these differences to a specific chemical class of human urinary metabolites. This and other work supports a functional role for urinary metabolites in innate antibacterial immunity. Clinical urinary pathogens posses numerous phenotypic and genetic adaptations to the urinary environment, suggesting multiple selective pressures related to urinary composition. Here we will identify human urinary metabolomic influences on UTI pathogenesis. Because human urine is a chemically complex biofluid, we will combine recent bioanalytical advances with contemporary data science approaches to identify metabolomic networks that influence bacterial growth and behavior. By identifying these networks, exploring their precise biochemical functions, and learning their physiologic origins we will provide a basis for translation to patient care. The proposed analyses and experiments represent a rigorous evaluation of our hypothesis that urinary composition plays an important role in infection resistance and should be targeted therapeutically to prevent or treat infections.