PDF(Pubmed)
Abstract：
Traditional folk treatments for the prevention and management of urinary tract infections (UTIs) and other infectious diseases often include plants and plant extracts that are rich in phenolic compounds. These have been ascribed a variety of activities, including inhibition of bacterial interactions with host cells. Here, we tested a panel of four well-studied phenolic compounds-caffeic acid phenethyl ester (CAPE), resveratrol, catechin, and epigallocatechin gallate-for the effects on host cell adherence and invasion by uropathogenic Escherichia coli (UPEC). These bacteria, which are the leading cause of UTIs, can bind and subsequently invade bladder epithelial cells via an actin-dependent process. Intracellular UPEC reservoirs within the bladder are often protected from antibiotics and host defenses and likely contribute to the development of chronic and recurrent infections. In cell culture-based assays, only resveratrol had a notable negative effect on UPEC adherence to bladder cells. However, both CAPE and resveratrol significantly inhibited UPEC entry into the host cells, coordinate with attenuated phosphorylation of the host actin regulator Focal Adhesion Kinase (FAK or PTK2) and marked increases in the numbers of focal adhesion structures. We further show that the intravesical delivery of resveratrol inhibits UPEC infiltration of the bladder mucosa in a murine UTI model and that resveratrol and CAPE can disrupt the ability of other invasive pathogens to enter host cells. Together, these results highlight the therapeutic potential of molecules like CAPE and resveratrol, which could be used to augment antibiotic treatments by restricting pathogen access to protective intracellular niches.IMPORTANCEUrinary tract infections (UTIs) are exceptionally common and increasingly difficult to treat due to the ongoing rise and spread of antibiotic-resistant pathogens. Furthermore, the primary cause of UTIs, uropathogenic Escherichia coli (UPEC), can avoid antibiotic exposure and many host defenses by invading the epithelial cells that line the bladder surface. Here, we identified two plant-derived phenolic compounds that disrupt activation of the host machinery needed for UPEC entry into bladder cells. One of these compounds, resveratrol, effectively inhibited UPEC invasion of the bladder mucosa in a mouse UTI model, and both phenolic compounds significantly reduced host cell entry by other invasive pathogens. These findings suggest that select phenolic compounds could be used to supplement existing antibacterial therapeutics by denying uropathogens shelter within host cells and tissues and help explain some of the benefits attributed to traditional plant-based medicines.
摘要：
用于预防和管理尿路感染(UTI)和其他传染病的传统民间治疗通常包括富含酚类化合物的植物和植物提取物。这些被归因于各种活动，包括抑制细菌与宿主细胞的相互作用。这里,我们测试了四个经过充分研究的酚类化合物-咖啡酸苯乙酯（CAPE），白藜芦醇,儿茶素,和表没食子儿茶素没食子酸酯-对泌尿致病性大肠杆菌（UPEC）的宿主细胞粘附和侵袭的影响。这些细菌,这是尿路感染的主要原因，可以通过肌动蛋白依赖性过程结合并随后侵入膀胱上皮细胞。膀胱内的细胞内UPEC储库通常受到抗生素和宿主防御的保护，并可能导致慢性和复发性感染的发展。在基于细胞培养的检测中，只有白藜芦醇对UPEC粘附膀胱细胞有显著的负面影响。然而,CAPE和白藜芦醇都显著抑制UPEC进入宿主细胞，与宿主肌动蛋白调节剂粘着斑激酶（FAK或PTK2）的磷酸化减弱协调，粘着斑结构的数量显着增加。我们进一步显示白藜芦醇的膀胱内递送抑制鼠UTI模型中膀胱粘膜的UPEC浸润,并且白藜芦醇和CAPE可以破坏其他侵入性病原体进入宿主细胞的能力。一起,这些结果突出了CAPE和白藜芦醇等分子的治疗潜力，它可以通过限制病原体进入保护性细胞内小生境来增强抗生素治疗。由于抗生素抗性病原体的持续增加和传播,尿路感染(UTI)异常常见并且越来越难以治疗。此外，尿路感染的主要原因，泌尿致病性大肠杆菌（UPEC），可以通过侵入膀胱表面的上皮细胞来避免抗生素暴露和许多宿主防御。这里,我们鉴定了两种植物衍生的酚类化合物,它们破坏UPEC进入膀胱细胞所需的宿主机制的激活.其中一种化合物，白藜芦醇,在小鼠UTI模型中有效抑制UPEC对膀胱粘膜的侵袭，和两种酚类化合物都显着减少了其他侵入性病原体进入宿主细胞。这些发现表明，选择酚类化合物可以通过拒绝宿主细胞和组织内的尿路病原体来补充现有的抗菌疗法，并有助于解释归因于传统植物性药物的一些益处。
