Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Urology, National Taiwan University Hospital, and National Taiwan University College of Medicine, Taipei, Taiwan.
J Microbiol Immunol Infect. 2024 Jun;57(3):385-395. doi: 10.1016/j.jmii.2024.02.007. Epub 2024 Feb 29.
Copper plays a role in urinary tract infection (UTI) and urinary copper content is increased during Proteus mirabilis UTI. We therefore investigated the effect of copper on uropathogenic P. mirabilis and the underlying mechanisms, focusing on the virulence associated aspects.
Mouse colonization, swarming/swimming assays, measurement of cell length, flagellin level and urease activity, adhesion/invasion assay, biofilm formation, killing by macrophages, oxidative stress susceptibility, OMPs analysis, determination of MICs and persister cell formation, RT-PCR and transcriptional reporter assay were performed.
We found that copper-supplemented mice were more resistant to be colonized in the urinary tract, together with decreased swarming/swimming, ureases activity, expression of type VI secretion system and adhesion/invasion to urothelial cells and increased killing by macrophages of P. mirabilis at a sublethal copper level. However, bacterial biofilm formation and resistance to oxidative stress were enhanced under the same copper level. Of note, the presence of copper led to increased ciprofloxacin MIC and more persister cell formation against ampicillin. In addition, the presence of copper altered the outer membrane protein profile and triggered expression of RcsB response regulator. For the first time, we unveiled the pleiotropic effects of copper on uropathogenic P. mirabilis, especially for induction of bacterial two-component signaling system regulating fitness and virulence.
The finding of copper-mediated virulence and fitness reinforced the importance of copper for prevention and therapeutic interventions against P. mirabilis infections. As such, this study could facilitate the copper-based strategies against UTI by P. mirabilis.
铜在尿路感染（UTI）中起作用，在奇异变形杆菌 UTI 期间尿铜含量增加。因此，我们研究了铜对尿路致病性奇异变形杆菌的影响及其潜在机制，重点关注与毒力相关的方面。
进行了小鼠定植、群集/游泳试验、细胞长度测量、鞭毛蛋白水平和脲酶活性、黏附/侵袭试验、生物膜形成、巨噬细胞杀伤、氧化应激易感性、OMPs 分析、MIC 和持久细胞形成的测定、RT-PCR 和转录报告基因测定。
我们发现，补充铜的小鼠在尿路中的定植能力更强，同时群集/游泳、脲酶活性、VI 型分泌系统的表达以及对尿路上皮细胞的黏附和侵袭能力降低，在亚致死铜水平下，奇异变形杆菌对巨噬细胞的杀伤能力增加。然而，在相同的铜水平下，细菌生物膜形成和对氧化应激的抵抗力增强。值得注意的是，铜的存在导致环丙沙星 MIC 增加，并对氨苄西林形成更多的持久细胞。此外，铜的存在改变了外膜蛋白谱，并触发了 RcsB 反应调节因子的表达。我们首次揭示了铜对尿路致病性奇异变形杆菌的多效性影响，特别是对调节适应性和毒力的细菌双组分信号系统的诱导。
铜介导的毒力和适应性的发现强调了铜在预防和治疗奇异变形杆菌感染中的重要性。因此，本研究可以促进基于铜的策略来对抗奇异变形杆菌引起的 UTI。
