《PLoS医学》：内部细菌导致尿路感染复发

David

尽管有适当的治疗和追踪调查，但那些患有尿道感染（UTI）的妇女依然有44%的几率在最初的感染发生后的1年内再次复发。在利用动物模型进行研究后，美国科学家日前在《公共科学图书馆－医学》（PLoS Medicine）上报告说，他们找到了证据，表明在UTI患者的膀胱中存在着细胞内的细菌小生境，这一发现对于传染病的复发研究及其治疗具有重要意义。
UTI最初由尿路致病性大肠埃希菌（UPEC）引起，每年大约有1300万名美国妇女被这种细菌感染，同时造成大量的经济损失以及发病率居高不下。通常认为，大多数复发感染是由来自排泄物细菌群落中最初感染的UPEC菌株的存留所导致的，这些菌株被认为能够回到并重新感染膀胱。然而密苏里州圣路易斯市华盛顿大学医学院的大卫·罗斯恩、斯科特·胡特葛丽恩和同事，通过对小鼠的研究提出了关于UPEC存留和UTI复发的另一个解释。在模型动物中，UPEC菌株入侵排列在膀胱上的上皮细胞并形成了细胞内的细菌群落（IBC）。一些被感染的上皮细胞随尿液排出，然而其他细胞依然能够释放细菌，其中许多细菌采用了一种细丝状的形态。这些细丝状的细菌能够抵抗宿主的免疫响应，最终，这些病原体建立了一种细胞内的存储形式，后者得到了抗生素和宿主免疫监督的保护。
为了研究这种动物模型与人类UTI的相关性，罗斯恩等人采集了80名患有急性无并发症膀胱炎的女性的尿样，以及20名曾有UTI史的无症状患者的尿样。利用一种光学显微镜、电子显微镜和抗体荧光染色的结合方法，研究人员在18%的膀胱炎患者中发现了IBC。在41%的患者尿样分析中发现了细丝状细菌，其中包括所有在尿液中发现了IBC的患者。无症状的病人和那些被革兰氏阳性病原体感染的患者则没有细丝状细菌或IBC。研究人员同时发现，所有具有IBC的患者和大多数在尿液中存在细丝状细菌的患者都被大肠埃希菌感染了。
研究人员认为，这项研究所发表的数据为IBC、细丝状细菌和急性无并发症膀胱炎之间的关系提供了一个有力的证据。这项工作同时表明，在鼠科动物模型中观察到的IBC感染循环至少与人类疾病是部分相关的。未来的研究将包括对采自不同时间点的尿样进行分析，从而评估IBC在UTI复发中扮演的准确角色，同时一项调查将涉及携带IBC的UTI患者是否能够从长期的抗菌素治疗或细胞内穿刺中获益。

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Detection of Intracellular Bacterial Communities in Human Urinary Tract InfectionDavid A. Rosen1, Thomas M. Hooton2, Walter E. Stamm3, Peter A. Humphrey4, Scott J. Hultgren1*
1 Department of Molecular Microbiology and Microbial Pathogenesis, Washington University School of Medicine, St. Louis, Missouri, United States of America, 2 Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America, 3 Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America, 4 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
Background Urinary tract infections (UTIs) are one of the most common bacterial infections and are predominantly caused by uropathogenic Escherichia coli (UPEC). While UTIs are typically considered extracellular infections, it has been recently demonstrated that UPEC bind to, invade, and replicate within the murine bladder urothelium to form intracellular bacterial communities (IBCs). These IBCs dissociate and bacteria flux out of bladder facet cells, some with filamentous morphology, and ultimately establish quiescent intracellular reservoirs that can seed recurrent infection. This IBC pathogenic cycle has not yet been investigated in humans. In this study we sought to determine whether evidence of an IBC pathway could be found in urine specimens from women with acute UTI.
Methods and Findings We collected midstream, clean-catch urine specimens from 80 young healthy women with acute uncomplicated cystitis and 20 asymptomatic women with a history of UTI. Investigators were blinded to culture results and clinical history. Samples were analyzed by light microscopy, immunofluorescence, and electron microscopy for evidence of exfoliated IBCs and filamentous bacteria. Evidence of IBCs was found in 14 of 80 (18%) urines from women with UTI. Filamentous bacteria were found in 33 of 80 (41%) urines from women with UTI. None of the 20 urines from the asymptomatic comparative group showed evidence of IBCs or filaments. Filamentous bacteria were present in all 14 of the urines with IBCs compared to 19 (29%) of 66 samples with no evidence of IBCs (p < 0.001). Of 65 urines from patients with E. coli infections, 14 (22%) had evidence of IBCs and 29 (45%) had filamentous bacteria, while none of the gram-positive infections had IBCs or filamentous bacteria.
Conclusions The presence of exfoliated IBCs and filamentous bacteria in the urines of women with acute cystitis suggests that the IBC pathogenic pathway characterized in the murine model may occur in humans. The findings support the occurrence of an intracellular bacterial niche in some women with cystitis that may have important implications for UTI recurrence and treatment.

Funding: This work was supported by National Institutes of Health Office of Research on Women's Health: Specialized Center of Research on Sex and Gender Factors Affecting Women's Health grant R01 DK64540, and National Institute of Diabetes and Digestive and Kidney Diseases grants R01 DK051406 and P01 DK53369. Funding organizations had no role in study design, data collection and analysis, decision to publish, or preparation of this manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Academic Editor: Steven M. Opal, Brown University School of Medicine, United States of America
Citation: Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ (2007) Detection of Intracellular Bacterial Communities in Human Urinary Tract Infection. PLoS Med 4(12): e329 doi:10.1371/journal.pmed.0040329
Received: June 25, 2007; Accepted: October 5, 2007; Published: December 18, 2007 Copyright: &copy; 2007 Rosen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abbreviations: IBC, intracellular bacterial community; SEM, scanning electron microscopy; TEM, transmission electron microscopy; UPEC, uropathogenic Escherichia coli; UTI, urinary tract infection; WBC, white blood cell
* To whom correspondence should be addressed. E-mail: hultgren@borcim.wustl.edu