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Medicine

建立和UTI和CAUTI表征在小鼠模型

Published: June 23, 2015
doi:
10.3791/52892
, , , ,
1Department of Molecular Microbiology and Center for Women’s Infectious Disease Research,Washington University School of Medicine

Summary

The ability to model urinary tract infections (UTI) is crucial in order to be able to understand bacterial pathogenesis and spawn the development of novel therapeutics. This work’s goal is to demonstrate mouse models of experimental UTI and catheter associated UTI that recapitulate and predict findings seen in humans.

Abstract

尿路感染（UTI）是非常普遍的，发病的一个显著原因，并且是对治疗日益耐抗生素。女性不成比例地被折磨UTI：所有妇女的50％将在其一生中的UTI。此外，这些妇女谁有一个初步的UTI将遭受复发与一些患有复发频繁，在生活，疼痛和不适，日常活动中断的质量严重恶化的20-40％，医疗费用增加，以及一些治疗方案等较长期抗生素预防。尿路致病性大肠杆菌 （统一企业）是社区获得性尿路感染的主要病原体。导管相关UTI（CAUTI）是最常见的医院获得性感染占一百万出现在每年美国和戏剧性的医疗费用。而统一企业也是CAUTI的首要原因，其他病原体是增加的意义，包括肠球菌粪。在这里，我们利用这一概括许多这些人类疾病的临床特点两个成熟的小鼠模型。对于尿路感染，一个C3H /纯模式概括了许多致病统一企业在包括人类宿主反应，IBC的形成和丝状观察到的特征。对于CAUTI，使用C57BL / 6小鼠，其保留导管膀胱植入一个模型，已被证明是容易受到与粪膀胱感染。这些代表车型被用来获得惊人的新的见解尿路感染的发病机制，这是导致新的治疗和管理或预防战略。

Introduction

尿路感染（尿路感染）是最常见的细菌感染中的一个，并可以分为基于采集，社区和医院获得性泌尿道感染的机制两类。社区获得性尿路感染常发生在其他方面健康的妇女，研究显示妇女大约50％将具有至少一个UTI在其一生中1。此外，复发是一个重大问题。谁拥有一个初始急性感染的妇女，尽管有适当的抗生素治疗，许多妇女继续有反复发作2具有半年内第二次感染的25-40％的机会。引起这类感染的细菌也日益抗生素有抗药性的进一步混杂的治疗方案3-6。每年UTI影响数以百万计的个人耗资约2.5十亿美元的医疗保健相关支出在美国，强调了疾病的影响和流行1,7 .Nosocomial收购尿路感染主要与外国机构，如留置导尿管的存在有关。导管相关尿路感染（CAUTI）仍然获得尿路感染最常见的院内，占〜这种感染8的70-80％。此外，CAUTI与增加的发病率和死亡率相关联，并且它是次要血流感染9的最常见原因。

尿路感染收购相关的统一企业社会被认为是由通过机械操纵引进细菌进入膀胱从水库在胃肠道性交，卫生条件差或不同主机之间的其它微生物种群动态过程中造成的生态位10。一旦膀胱内，UPEC雇用许多毒力因子，包括胶囊，铁采集系统，毒素，毒力质粒的tRNA，致病岛和已被证明在发病中发挥作用定居因子<SUP> 11-14。关键要建立UPEC殖民化，统一企业也编码多种类型的胶粘剂伴侣迎来通路（CUP）菌毛识别受体的特异性立体15。 1型菌毛，放倒与FimH粘附，是由统一企业表达并结合甘露糖基uroplakins 16和α-1，β-3整联17，其被表达在人和小鼠囊18的腔表面。这些FimH介导的互动有利于细菌的定植和入侵的浅表上皮细胞19,20。一旦进入细胞，UPEC可以逃逸到细胞质其中单个细菌可以快速分裂，以形成细胞内细菌群落（IBC），其在成熟化，可以含有约10 4细菌21。 IBC形成已被证明在至少六个不同的小鼠品系，C3H / HeN系，C3H / HeJ小鼠，C57BL / 6，CBA，FVB / NJ和BALB / c，和与多种不同UPE的ç株和其他肠杆菌科22-24。然而IBC形成时空差异可以根据鼠标背景和感染UPEC应变而变化。在C3H /感染的典型UPEC HeN小鼠品系UTI89或CFT073，IBC形成可以早在3 HPI（小时后感染）可视化细菌的生物量小。该社区的不断扩大和达到的发展约6 HPI一个“中点”当棒状细菌占据终末分化肤浅伞细胞的细胞质空间的大百分比这些早期中型散货形式与显示类似的尺寸多数相对同步的方式和形态。 〜8 HPI的细菌从一个杆菌IBC变化球菌形态。中型散货箱是一过性的。因此，从12-18 HPI导致细菌群体的不断扩大IBC成熟，其次是他们的成丝和扩散出细胞的Wi随后日蔓延到相邻小区23。因此，IBC利基允许快速的细菌生长在从宿主免疫应答和抗生素25保护的环境。被UPEC感染所看到小鼠不同的阶段也观察到在人中，如中型散货和成丝，支持尿路感染的小鼠模型，可用于模拟UTI在人类22,26-28一个有益的工具。

虽然大多数女性体验UTI在其一生中，这些感染的结果可以从急性自限性感染无复发，频繁复发膀胱炎。此外，研究表明UTI强烈家族性发生，这表明遗传成分有助于UTI易感性29。我们已发现，看到在诊所的不同的UTI结果可以通过实验UPEC感染之间的近交小鼠品系30的不同的结果进行镜像。例如，C3H /母鸡，CBA，DBA和C3H / HeOuJ小鼠易感，在感染性剂量依赖性方式，以持久，慢性膀胱炎特征在于持久性，高滴度菌（> 10 4集落形成单位（CFU）/ ml）的高滴度细菌膀胱负担在牺牲>后4周感染（WPI），慢性炎症，和尿路上皮坏死。这些小鼠也显示，IL-6，G-CSF，KC，和IL-5的前24 HPI内升高的血清水平是作为生物标志物用于治疗慢性膀胱炎的发展。这可准确地表示UTI的自然过程在一些妇女，作为安慰剂的研究表明，妇女经历后膀胱炎的最初症状的UTI将保留在他们的尿高水平细菌数周的大百分比，如果不给予抗生素治疗31 32。此外，使用C3H / HeN小鼠中，我们发现，慢性膀胱炎的历史是用于随后的严重反复感染一个显著危险因素。复发性尿路感染是最SIUTI和C3H /纯鼠标gnificant临床表现是目前唯一研究模式，概括先前曝光后增加的倾向。第二UTI结局概括在C57BL / 6小鼠急性那里感染统一企业是自限性，与膀胱炎和菌大约在一个星期内解决。有趣的是，在这种模式下，UPEC容易形成内膀胱组织静止的细胞内储从中UPEC能够从休眠状态出现重新发起活性UTI，可能解释一种机制用于 ​​同一菌株复发性尿路感染在人中33,34。

除了上尿路感染易感性的遗传影响，引入导管插入膀胱大大增加具有感染以及增加的细菌能够引起感染的范围的可能性。已经证实，人类导尿引起组织学和由于机械应力，结果在一个健壮的炎症反应，剥脱，固有层和submucusa，尿路上皮变薄的水肿，尿路上皮和肾脏35,36的粘膜损伤的免疫学变化膀胱。此外，该导管提供用于细菌附着从而产生由几个物种用来使CAUTI的环境中的表面。而统一企业仍然是一个主要因素， 粪肠球菌占这些CAUTI 37的15％。E.粪变得对抗生素耐药越来越具有耐万古霉素的出现，构成了严重的健康问题38。E.肠球菌具有许多毒力因子，包括毒素和必要的附件二者导管和上皮38粘附。期间导尿，宿主是易受微生物附着，繁殖和传播，在泌尿道39,40。E. faeca利斯形成在导管生物膜作为一个机构的一部分，以坚持在膀胱和传播对肾脏，这是再生在小鼠CAUTI模型41。最近，已经在导尿所示，纤维蛋白原（纤维蛋白原）被释放到膀胱的炎症反应的一部分。蛋白原积聚在膀胱，大衣的导管，是必需成分为E.粪肠球菌生物膜的形成，运作作为附件支架。在CAUTI的C57BL / 6小鼠模型中，我们发现， 大肠杆菌肠球菌生物膜形成的导管，并因此持久性膀胱，是依赖于EBP菌毛 ​​，特别是其前端粘附EBPA。我们发现，EBPA的N-末端结构域特异性结合FG涂覆导管。此外，人们发现， 大肠杆菌利用粪作为纤维蛋白原期间感染源 ​​代谢产物，从而提高生物膜形成42。

小鼠模型已经证明关键understanding以及预测和UTI 41 CAUTI临床表现。在这篇文章中，我们证明接种物制备的膀胱炎UPEC的隔离UTI89和经尿道接种C3H / HeN小鼠的。此外，我们展示了一个协议，用于导管插入大肠杆菌的C57BL / 6小鼠和接种OG1RF 粪应变。这两种技术导致一致的和可靠的UTI或CAUTI小鼠。我们还显示用于急性膀胱炎和尿液收集用于治疗慢性或复发性膀胱炎的分析，观察IBC形成技术。 C3H / HeN小鼠已被用于研究统一企业发病机制方面，包括最初的细菌的入侵，形成IBC，成丝和慢性膀胱炎23,33,43的发展。这些毒力参数也已研究了在各种其他小鼠背景22,33。对于CAUTI的C57BL / 6模型允许异物植入，随后细菌共同膀胱电离，从而可以维持7天感染后41。这些模型已经用于评估细菌毒力机制，宿主对尿路感染和机制，以颠覆宿主反应，其中大部分已被随后概括或临床人群中观察到的有用。

Protocol

伦理声明：华盛顿大学动物研究委员会批准所有的鼠标感染和程序的协议号20120216，这是批准2013年1月11日，截止2016年1月11日部分。整体护理的动物是有照顾和实验动物从国家研究委员会和美国农业部的动物保健资源指南的指导使用一致的。安乐死程序与一致“的动物版本2013的安乐死AVMA准则。” 1.统一企业UTI协议，接种针准备（图S1） 卸下地下30针帽。线程大约1英寸P…

Representative Results

简单和导管相关UTI的膀胱内的模型提供了灵活的平台，阐明细菌发病机理，宿主组织上这些疾病的影响，以及发展和新的方法测试的分子机制来管理这些常见和昂贵的感染。根据小鼠品系和病原体，膀胱内接种可用于研究宿主-病原体相互作用阐明必要用于发起或调节急性因素（ 图1和3），慢性或复发性（ 图2）膀胱炎。在图1中所示的数据是代表?…

Discussion

单纯性社区获得性尿路感染是一种常见的和昂贵的感染占每年46几万元的初级保健访问。此外，CAUTIs是一种常见的医疗获得性感染，已成为极其昂贵的医疗保健提供商医疗保险和医疗补助服务中心不再报销提供商用于治疗从医院获得45 CAUTI会带来额外的成本。 UTI，既单纯性膀胱炎和CAUTI的小鼠模型中，在这些协议中描述提供了宝贵的工具用于理解所必需的启动，维持和调节的几种?…

Disclosures

The authors have nothing to disclose.

Acknowledgements

资助这项工作是由ORWH SCOR P50 DK064540提供，RO1 DK 051406，RO1 AI 108749-01，F32 DK 101171，和F32 DK 104516-01。

Materials

Material for catheter and needle preparation:
30ga needles BD Precision Glide 305106 30Gx ½ (0.3 mm x 13mm)
PE10 polyethylene tubing BD 427400 Inside diameter -0.011 in (0.28 mm); outside diameter – 0.024 in (0.61 mm)
RenaSIL 025 platinum cured silicon tubing Braintree Scientific, Inc SIL 025 inside diameter-0.012 x outside diameter 0.025, 25 ft coil
Material for infections:
Isoflourane – Isothesia Butler Schein 29405 250 mL
Clear Glass Straight-Sided Jar Kimble Chase 5413289V 21
Stainless Steel Tea Infuser Schefs-Amazon Premium Loose Leaf Tea Infuser By Schefs – Stainless Steel – Large Capacity –
Non-sterile cotton balls Fisherbrand 22-456-880
50 ml Falcon tubes VWR 89039-660
Isotec 3 -vaporizer Ohmeda 1224478
Ear punch Fisher Scientific 13-812-201 (when necessary)
Betadine solution Betadine solution 10% Povidie-iodine topical solution
Q-tips Fisher Scientific 22-037-924 6 in
Diapers for bench Fisherbrand 14206 63 Absorbent Underpads (20”X36”mats)
Surgical lubricant Surgilube 0281-0205-36
Dissecting scissor Fine Science tools, INC 14084-08
Micro-Adson Forceps Fine Science tools, INC 11018-12
1 ml syringe BD 309659 Tuberculin slip tip
Parafilm Bemis PM996 4 in x 125 FT
Eppendorf rack Fisherbrand 05-541-1
Eppendorf tubes MIDSCI AVX-T-17-C
Harvesting catheters, bladders and kidneys:
Homogenizer PRO Scientific INC Bio-Gen Pro 200
5 ml polypropylene round-bottom tube BD 352063 for organ homogenization
Paper towel Georgia-Pacific
Ethanol Pharmco-AAPER 11100020S 200 proof
Costar™ Clear Polystyrene 96-Well Plates Corning 3788
1X Phosphate sodium saline Sigma-Aldrich P3813
BRANSONIC Ultrasonic cleaner 1210 Branson Ultrasonics Corporation 1210
IBC materials:
6-well tissue culture test plate Techno Plastic Products 92006
Pins Fine Science Tools 26002-20
Sylgard 184 Dow Corning 3097358-1004 Silicone Elastomer Kit
X-gal (5-bromo-4-chloro-3-indolyl-b-D-galactoside) Invitrogen 15520-034 Ultrapure
N, N-Dimethylformamide Sigma Aldrich D4551
MgCl2 (Magnesium chloride) Sigma Aldrich M8266
Sodium deoxycholate Sigma Aldrich D6750
Nonidet-P40 Roche 11754599001 Octylphenolpoly(ethyleneglycolether)n
Potassium hexacyanoferrate(II) trihydrate (K-ferrOcyanide) Sigma Aldrich P3289
Potassium hexacyanoferrate(III) (K-ferrIcyanide) Sigma Aldrich 60299
DOWNLOAD MATERIALS LIST

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Urinary Tract InfectionUTICatheter-associated UTICAUTIUropathogenic Escherichia ColiUPECEnterococcus FaecalisMouse ModelPathogenesisVirulenceHost ResponseIntracellular Bacterial CommunityIBCFilamentationAntibiotic ResistanceRecurrenceTreatmentPrevention
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Conover, M. S., Flores-Mireles, A. L., Hibbing, M. E., Dodson, K., Hultgren, S. J. Establishment and Characterization of UTI and CAUTI in a Mouse Model. J. Vis. Exp. (100), e52892, doi:10.3791/52892 (2015).
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