Bladder Exposure to Gardnerella Activates Host Pathways Necessary for Escherichia coli Recurrent UTI.
Bladder Exposure to Gardnerella Activates Host Pathways Necessary for Escherichia coli Recurrent UTI.
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DOI：
10.3389/fcimb.2021.788229
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发表时间：
2021
影响因子：
5.7
通讯作者：
Gilbert NM
中科院分区：
文献类型：
--
作者：
O'Brien VP;Lewis AL;Gilbert NM
复发性尿路感染（rUTI）是一个代价高昂的临床问题，每年影响全世界数百万妇女。大多数rUTI病例是由尿路致病性大肠杆菌（UPEC）引起的。来自人类和小鼠模型的数据表明，一些rUTI病例是由膀胱潜伏库中出现的upc引起的。阴道生态失调的妇女，典型特征是高水平的加德纳菌和其他厌氧菌，尿路感染的风险增加。多项研究在经尿道导尿（以限制阴道污染）收集的尿液中检测到加德纳菌，这表明一些妇女在尿路中经常接触加德纳菌。我们最近报道了在小鼠模型中，将加德纳菌接种到膀胱中会触发UPEC膀胱储存器中的rUTI。在这里，我们进行了全膀胱rna测序，以确定参与加德纳菌诱导rUTI的宿主途径。我们发现了多种宿主途径在加德纳菌暴露后在整个膀胱中差异表达，如炎症/免疫和上皮细胞转换的途径。在基因水平上，我们发现了即时早期（IE）基因的上调，这是在感染和炎症等刺激后不久在各种细胞类型中诱导的。其中一个上调的IE基因是孤儿核受体Nur77（又名Nr4a1）。在Nur77-/-小鼠中进行的初步实验表明，Nur77是暴露于Gardnerella以触发UPEC水库rUTI所必需的。这些发现表明膀胱基因表达可以受到短期暴露于泌尿生殖细菌的影响，并为未来在不同细胞类型（如单细胞转录组学技术）中的反应进行检查提供了依据。在Nur77-/-小鼠中的生物学验证研究为进一步研究Nur77和rUTI中的即时早期反应奠定了基础。
Recurrent urinary tract infections (rUTI) are a costly clinical problem affecting millions of women worldwide each year. The majority of rUTI cases are caused by uropathogenic Escherichia coli (UPEC). Data from humans and mouse models indicate that some instances of rUTI are caused by UPEC emerging from latent reservoirs in the bladder. Women with vaginal dysbiosis, typically characterized by high levels of Gardnerella and other anaerobes, are at increased risk of UTI. Multiple studies have detected Gardnerella in urine collected by transurethral catheterization (to limit vaginal contamination), suggesting that some women experience routine urinary tract exposures. We recently reported that inoculation of Gardnerella into the bladder triggers rUTI from UPEC bladder reservoirs in a mouse model. Here we performed whole bladder RNA-seq to identify host pathways involved in Gardnerella-induced rUTI. We identified a variety host pathways differentially expressed in whole bladders following Gardnerella exposure, such as pathways involved in inflammation/immunity and epithelial turnover. At the gene level, we identified upregulation of Immediate Early (IE) genes, which are induced in various cell types shortly following stimuli like infection and inflammation. One such upregulated IE gene was the orphan nuclear receptor Nur77 (aka Nr4a1). Pilot experiments in Nur77-/- mice suggest that Nur77 is necessary for Gardnerella exposure to trigger rUTI from UPEC reservoirs. These findings demonstrate that bladder gene expression can be impacted by short-lived exposures to urogenital bacteria and warrant future examination of responses in distinct cell types, such as with single cell transcriptomic technologies. The biological validation studies in Nur77-/- mice lay the groundwork for future studies investigating Nur77 and the Immediate Early response in rUTI.
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影响因子：
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影响因子：
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