Department of Biology, University of Louisiana at Lafayettegrid.266621.7, Lafayette, Louisiana, USA.
Lodo Therapeutics, New York, NY, USA.
mSphere. 2022 Jun 29;7(3):e0000422. doi: 10.1128/msphere.00004-22. Epub 2022 Apr 28.
Uropathogenic Escherichia coli (UPEC) is the principal etiology of more than half of urinary tract infections (UTI) in humans with diabetes mellitus. Epidemiological data and studies in mouse model of ascending UTI have elucidated various host factors responsible for increasing the susceptibility of diabetic hosts to UPEC-UTI. In contrast, diabetic urinary microenvironment-mediated alterations in UPEC physiology and its contributions to shaping UPEC-UTI pathogenesis in diabetes have not been examined. To address our central hypothesis that glycosuria directly induces urinary virulence of UPEC, we compared virulence characteristics and gene expression in human UPEC strains UTI89 (cystitis) and CFT073 (pyelonephritis), exposed for 2 h to urine from either male or female donors that was either plain or supplemented with glucose to mimic glycosuria. Compared to control UPEC exposed to nutrient-rich culture medium, lysogeny broth, glycosuria-exposed UPEC exhibited significant increase in biofilm formation and reduction in the hemagglutination of Guinea pig erythrocytes (a measure of type 1 piliation). In addition, the analysis of UTI89 transcriptome by RNA sequencing revealed that 2-h-long, exposure to glycosuria also significantly alters expression of virulence and metabolic genes central to urinary virulence of UPEC. Addition of galactose as an alternative carbon source affected biofilm formation and gene expression profile of UPEC to an extent similar to that observed with glucose exposure. In summary, our results provide novel insights into how glycosuria-mediated rapid changes in UPEC fitness may facilitate UTI pathogenesis in the diabetic urinary microenvironment. Uropathogenic Escherichia coli (UPEC) is an important causative agent of urinary tract infections in diabetic humans. We examined the effects of exposure to glycosuria (presence of glucose in urine) on the virulence and gene expression by UPEC. Our results show that glycosuria rapidly (in 2 h) alters UPEC gene expression, induces biofilm formation, and suppresses type 1 piliation. These results offer novel insights into the pathogenesis of UPEC in the urinary tract.
尿路致病性大肠杆菌（UPEC）是导致糖尿病患者半数以上尿路感染（UTI）的主要病原体。流行病学数据和上行性 UTI 小鼠模型研究阐明了各种宿主因素，这些因素导致糖尿病宿主易患 UPEC-UTI。相比之下，糖尿病尿液微环境介导的 UPEC 生理学改变及其对糖尿病 UPEC-UTI 发病机制的影响尚未得到研究。为了验证我们的中心假设，即糖尿导致 UPEC 的尿液毒力直接增加，我们比较了暴露于男性或女性供体尿液中 2 小时的 UPEC 菌株 UTI89（膀胱炎）和 CFT073（肾盂肾炎）的毒力特征和基因表达，尿液中含有葡萄糖以模拟糖尿，或者不含葡萄糖作为对照。与暴露于富含营养的培养基的对照 UPEC 相比，暴露于糖尿的 UPEC 的生物膜形成显著增加，豚鼠红细胞的血凝作用（1 型菌毛的测量）显著降低。此外，通过 RNA 测序对 UTI89 的转录组进行分析表明，暴露于糖尿 2 小时还显著改变了 UPEC 尿液毒力的中心毒力和代谢基因的表达。添加半乳糖作为替代碳源，对 UPEC 的生物膜形成和基因表达谱的影响与葡萄糖暴露相似。总之，我们的研究结果为糖尿介导的 UPEC 适应性快速变化如何促进糖尿病尿液微环境中的 UTI 发病机制提供了新的见解。
