Urinary tract infection (UTI) is a prominent global health care burden. Although UTI is readily treated with antibiotics in healthy adults, complicated cases in immune-compromised individuals and the emerging antibiotic resistance of several uropathogens have accelerated the need for new treatment strategies. Here, we surveyed the composition of urinary exosomes in a mouse model of uropathgenic Escherichia coli (UPEC) UTI to identify specific urinary tract defense constituents for therapeutic development. We found an enrichment of the iron-binding glycoprotein lactoferrin in the urinary exosomes of infected mice. In subsequent in vitro studies, we identified human bladder epithelial cells as a source of lactoferrin during UPEC infection. We further established that exogenous treatment with human lactoferrin (hLf) reduces UPEC epithelial adherence and enhances neutrophil antimicrobial functions including bacterial killing and extracellular trap production. Notably, a single intravesicular dose of hLf drastically reduced bladder bacterial burden and neutrophil infiltration in our murine UTI model. We propose that lactoferrin is an important modulator of innate immune responses in the urinary tract and has potential application in novel therapeutic design for UTI.

中文翻译：

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泌尿乳铁蛋白的增强增强了致病性大肠杆菌的宿主固有免疫清除率。

尿路感染（UTI）是全球医疗保健的主要负担。尽管在健康的成年人中很容易用抗生素治疗UTI，但免疫功能低下的个体中的复杂病例以及几种尿路病原体对抗生素的耐药性加速了对新治疗策略的需求。在这里，我们调查了泌尿致病性大肠杆菌（UPEC）UTI小鼠模型中尿液外泌体的组成，以确定用于治疗开发的特定尿路防御成分。我们发现感染小鼠的泌尿外泌体中铁结合糖蛋白乳铁蛋白的富集。在随后的体外研究中，我们确定了人膀胱上皮细胞是UPEC感染期间乳铁蛋白的来源。我们进一步确定，用人乳铁蛋白（hLf）进行外源治疗可降低UPEC上皮粘附并增强中性粒细胞抗菌功能，包括杀死细菌和产生细胞外诱集物。值得注意的是，在我们的鼠类UTI模型中，单囊内注射hLf可以大大减少膀胱细菌负担和中性粒细胞浸润。我们建议，乳铁蛋白是泌尿道先天免疫反应的重要调节剂，在尿路感染的新型治疗设计中具有潜在的应用价值。