Roles of vaginal bacteria in bladder exfoliation and recurrent UTI

项目总结 尿路感染(UTI)是一个影响全球数百万女性的昂贵的临床问题。临床研究 与细菌性阴道病(BV)有关--一种阴道微生物区系的失衡--增加了对 不同的UTI结果，但实验模型没有解释潜在的机制。其中一个 尿路感染的最大危险因素是频繁和/或最近的性行为。很可能阴道细菌是 通常在性生活活跃的女性中被引入膀胱。事实上，有几种阴道细菌--大多数 常见阴道加德纳氏菌(G.V.)和卷曲乳杆菌(Lactobacilluscrispatus(L.C.) 通过针吸直接从膀胱采集。通用汽车。在BV期间被发现处于高水平。虽然文化 通常情况下不会检测到它，它在尿液中的存在与复发史有关。 Uti(Ruti)。L.C.被广泛认为是一种“健康的”阴道细菌，通常是从健康的 无下尿路症状的女性。我们的新老鼠模型表明，当G.V.获得访问 尿路，它会触发膀胱上皮的脱落。当小鼠怀有潜伏的细胞内膀胱时 E.C.的蓄水池，膀胱暴露于G.V.触发了E.C.Exress和Ruti的速度是前者的4倍 暴露于单独的车辆或L.C.重要的是，通用汽车。曝光被主办方和 到E.C.的时候，有机体已经不在了。鲁蒂出现了。这些数据表明，膀胱暴露在 阴道细菌可以是暂时的，但对膀胱的病理生理有显著影响，并提供了一种潜在的 BV和UTI之间的联系的解释。在这项提案中，我们将追求两个目标，以了解其他 阴道细菌可能会促进或减轻G.V.的负面影响。在膀胱里。AIM 1将调查 L.C.能预防G.V.引起的膀胱脱落和E.C.鲁蒂。这一点特别相关，因为L.C.经常是 在最近的文献中被称为“保护性的”，在临床上是基于对膀胱的关联。我们的研究将 直接在实验系统中解决这种可能性。目标2将定义人类阴道的各个方面 微生物组组成影响女性的膀胱脱落，并检查G.V.本机内的行为 社区会导致剥落和E.C.在小鼠体内出现。在老鼠身上进行的实验也将揭示 除了G.V.之外的分类群。对膀胱的这些影响有一定的作用。成功完成这些任务 研究将揭示细菌致病的新范式，并提供新的见解，为未来提供信息 努力治疗和预防汝提。

PROJECT SUMMARY Urinary tract infection (UTI) is a costly clinical problem that affects millions of women worldwide. Clinical studies implicate bacterial vaginosis (BV)—an imbalance of the vaginal microbiota—in enhancing susceptibility to different UTI outcomes, but experimental models have not explained the underlying mechanisms. One of the strongest risk factors for UTI is frequent and/or recent sexual activity. It is likely that vaginal bacteria are commonly introduced into the bladder in sexually active women. Indeed, several vaginal bacteria—most frequently Gardnerella vaginalis (G.v.) and Lactobacillus crispatus (L.c.)— have been isolated from urine collected directly from the bladder by needle aspiration. G.v. is found at high levels during BV. Although culture conditions are not often poised to detect it, its presence in urine has been associated with a history of recurrent UTI (rUTI). L.c. is widely regarded as a “healthy” vaginal bacterium and is most often isolated from healthy women without lower urinary tract symptoms. Our new mouse model shows that when G.v. gains access to the urinary tract, it triggers exfoliation of the bladder epithelium. When mice harbored latent intracellular bladder reservoirs of E.c., bladder exposures to G.v. triggered E.c. egress and rUTI at a 4-times higher rate compared to exposures to vehicle alone or L.c. Importantly, G.v. exposures were cleared rapidly by the host and the organism was absent by the time E.c. rUTI took place. These data demonstrate that exposures of the bladder to vaginal bacteria can be transient, yet have a marked effect on bladder pathophysiology, and provide a potential explanation for the link between BV and UTI. In this proposal, we will pursue two aims to understand how other vaginal bacteria may promote or mitigate the negative effects of G.v. in the bladder. Aim 1 will investigate whether L.c. can prevent G.v.-induced bladder exfoliation and E.c. rUTI. This is particularly relevant because L.c. is often referred to in the recent literature as “protective” in the bladder based on clinical associations. Our studies will address this possibility directly in an experimental system. Aim 2 will define how aspects of human vaginal microbiome composition influence bladder exfoliation in women and examine how G.v. acts within native communities to cause exfoliation and E.c. emergence in mice. Experiments in mice also will reveal whether taxonomic groups in addition to G.v. contribute to these effects in the bladder. Successful completion of these studies will uncover new paradigms in bacterial pathogenesis and provide novel insights that will inform future efforts to treat and prevent rUTI.