Copper Is a Host Effector Mobilized to Urine during Urinary Tract Infection To Impair Bacterial Colonization
Copper Is a Host Effector Mobilized to Urine during Urinary Tract Infection To Impair Bacterial Colonization
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DOI：
10.1128/iai.01041-16
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发表时间：
2017-03-01
影响因子：
3.1
通讯作者：
Subashchandrabose, Sargurunathan
中科院分区：
文献类型：
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作者：
Hyre, Amanda N.;Kavanagh, Kylie;Subashchandrabose, Sargurunathan
尿路感染（UTI）是一种全球性的主要传染病，每年影响数百万人。尿路致病性大肠杆菌（UPEC）引起的尿路感染期间，人尿铜（Cu）含量升高。UPEC上调患者临床UTI期间Cu外排基因的表达，作为对宿主来源的Cu的适应性反应。铜是否被动员到尿中作为对UTI的宿主反应及其在保护免受UTI中的作用仍未解决。为了解决这些问题，我们测试了一个假设，即铜是一个主机效应器动员到尿中UTI期间，以限制细菌的生长。我们的研究结果表明，铜被动员到尿中尿路感染引起的主要尿路病原体奇异变形杆菌和肺炎克雷伯菌，除了UPEC，在人类。铜蓝蛋白是一种含铜铁氧化酶，在UTI尿液中的水平高于健康对照尿液，并在UTI期间作为尿铜的分子来源。我们的研究结果表明，血浆铜蓝蛋白通过转铁蛋白依赖性机制降低尿中铁的生物利用度。在非人灵长类动物中使用UPEC的实验性UTI重现了临床UTI期间观察到的尿Cu含量增加。此外，铜缺乏的小鼠高度定植UPEC，表明铜参与限制细菌生长的尿路内。总的来说，我们的研究结果表明，铜是一个主机效应器，参与保护免受病原体定植的尿路。由于尿铜水平是服从调制，增强铜为基础的主机防御UTI代表了一种新的方法来限制细菌定植在UTI。
Urinary tract infection (UTI) is a major global infectious disease affecting millions of people annually. Human urinary copper (Cu) content is elevated during UTI caused by uropathogenic Escherichia coli (UPEC). UPEC upregulates the expression of Cu efflux genes during clinical UTI in patients as an adaptive response to host-derived Cu. Whether Cu is mobilized to urine as a host response to UTI and its role in protection against UTI remain unresolved. To address these questions, we tested the hypothesis that Cu is a host effector mobilized to urine during UTI to limit bacterial growth. Our results reveal that Cu is mobilized to urine during UTI caused by the major uropathogens Proteus mirabilis and Klebsiella pneumoniae, in addition to UPEC, in humans. Ceruloplasmin, a Cu-containing ferroxidase, is found at higher levels in UTI urine than in healthy control urine and serves as the molecular source of urinary Cu during UTI. Our results demonstrate that ceruloplasmin decreases the bioavailability of iron in urine by a transferrin-dependent mechanism. Experimental UTI with UPEC in nonhuman primates recapitulates the increased urinary Cu content observed during clinical UTI. Furthermore, Cu-deficient mice are highly colonized by UPEC, indicating that Cu is involved in the limiting of bacterial growth within the urinary tract. Collectively, our results indicate that Cu is a host effector that is involved in protection against pathogen colonization of the urinary tract. Because urinary Cu levels are amenable to modulation, augmentation of the Cu-based host defense against UTI represents a novel approach to limiting bacterial colonization during UTI.