Harnessing Antibody Responses to Prevent and Treat Urinary Tract Infections
利用抗体反应预防和治疗尿路感染
基本信息
- 批准号:10344461
- 负责人:
- 金额:$ 63.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-11-10 至 2026-10-31
- 项目状态:未结题
- 来源:
- 关键词:Activities of Daily LivingAddressAdherenceAffectAffinityAnimal ModelAnimalsAntibiotic ResistanceAntibiotic TherapyAntibioticsAntibodiesAntibody FormationAntibody ResponseAntibody SpecificityAreaB-LymphocytesBacterial AdhesinsBindingBladderBlocking AntibodiesCellsCoalCommunicable DiseasesCommunitiesCystitisDataDevelopmentDiagnosticDistalEpithelialEpitopesEquilibriumEscherichia coliExtended-spectrum β-lactamaseGastrointestinal tract structureGenerationsGenomeGnotobioticHost Defense MechanismHumanImmuneImmune System DiseasesImmunizationImmunoglobulin GImmunoglobulin-Secreting CellsImpairmentInfection preventionInvadedLightMannoseMannosidesMediatingModelingMolecular ConformationMonkeysMonoclonal AntibodiesMucous MembraneMulti-Drug ResistanceMusMutationOperonOralOral AdministrationPassive ImmunizationPathogenesisPathogenicityPatientsPersonsPhase Ia/Ib Clinical TrialPilumPrevalencePreventionProductionPublic HealthRecombinantsRecurrenceResearchResistanceResolutionRoleSeedsSerinusSignal TransductionSpecificitySurfaceTertiary Protein StructureTestingTherapeuticTherapeutic UsesThinkingTimeUnited StatesUrinary tractUrinary tract infectionUrineUropathogenUropathogenic E. coliVaccinatedVaccinationVaccinesVirus DiseasesWomanascending urinary tract infectionbacterial communitybasecancer therapycombatdesigneffectiveness testingfluoroquinolone resistancegut colonizationgut microbiotahuman monoclonal antibodieshumanized monoclonal antibodiesin vivomicrobial communitymouse modelmucosal vaccinationpreventreceptorresistant strainresponse
项目摘要
SUMMARY
Urinary tract infections (UTIs) affect 15 million women in the United States every year and treatment for UTIs is
becoming more difficult due to high rates of antibiotic resistance. Further, UTIs are highly recurrent. Between 20
and 40% of UTI episodes are followed by recurrent UTIs (rUTIs), with some women suffering as many as 6 or
more recurrences per year. Uropathogenic Escherichia coli (UPEC) is the major causative agent of UTIs.
Antibiotic resistance within UPEC isolates is rising, and the emergence of extended-spectrum beta-lactamase
producing and fluoroquinolone resistant strains is a serious public health concern. Type 1 pili, tipped with the
mannose binding FimH adhesin have been shown to be essential for bladder colonization and UTI pathogenesis
in multiple mouse models. FimH mediates binding to mannosylated uroplakins lining the bladder surface to
facilitate colonization and invasion into bladder cells where they rapidly replicate into intracellular bacterial
communities that protect UPEC from immune cells and antibiotics. In addition, FimH facilitates the ability of
UPEC to establish a reservoir in the GIT, from where they can seed UTIs by ascending from the periurethral
area into the bladder. While UPEC are genetically variable, FimH is part of the core E. coli genome, although
rare strains have been found with mutations in the type 1 operon. Immunization against FimH protects against
UPEC UTI in murine and monkey cystitis models and a FimH-based vaccine has been allowed by the FDA for
patients suffering from multi-drug resistant UPEC. In animal models, protection is antibody-mediated, as FimH-
specific IgG antibodies are found in the urine from protected animals and can protect from UTI through passive
transfer. Intriguingly, UPEC abundance in the gut is increased at the time of symptomatic UTI, suggesting that
gut colonization is a key step in the rUTI cycle. Additionally, studies in this proposal show that eliciting a mucosal
antibody response against FimH can reduce UPEC colonization of the gut. In light of these findings, this proposal
addresses the hypothesis that anti-FimH induced antibodies can combat rUTI by two distinct mechanisms: i)
prevention of UPEC binding to the uroepithelium; and ii) interference with UPEC colonization of the GIT, thereby
lowering the likelihood of UPEC introduction into the urinary tract. The aims of this proposal are to: i) determine
how mucosal vaccination against FimCH reduces UPEC gut colonization (Aim 1); ii) exploit vaccine induced B
cell responses to isolate monoclonal antibodies (mAbs) to FimH and determine their epitope specificity (Aim 2);
and iii) use these mAbs in mouse models of GIT colonization and cystitis in order to elucidate mechanisms of
protection (Aim 3). The research plan will unravel the mechanisms by which anti-FimH antibodies may function
to prevent UTIs by directly blocking bladder binding and indirectly by interfering with UPEC GIT colonization.
These results will inform the rational targeting of the uropathogens that affect millions of people with rUTIs. In
addition, our approach enables the rapid generation of anti-UPEC human mAbs that can be used for therapeutics
and diagnostics.
概括
尿路感染 (UTI) 每年影响美国 1500 万女性,尿路感染的治疗方法
由于抗生素耐药性高,变得更加困难。此外,尿路感染的复发率很高。 20 之间
40% 的尿路感染发作后会出现复发性尿路感染 (rUTI),一些女性遭受多达 6 或
每年复发次数更多。尿路致病性大肠杆菌 (UPEC) 是尿路感染的主要病原体。
UPEC 分离株内的抗生素耐药性正在上升,并且出现了超广谱 β-内酰胺酶
产生氟喹诺酮类药物和耐药菌株是一个严重的公共卫生问题。 1 型菌毛,尖端带有
甘露糖结合 FimH 粘附素已被证明对于膀胱定植和 UTI 发病机制至关重要
在多种鼠标模型中。 FimH 介导与膀胱表面内衬的甘露糖化尿斑蛋白的结合
促进膀胱细胞的定植和侵袭,并在膀胱细胞中快速复制成细胞内细菌
保护 UPEC 免受免疫细胞和抗生素侵害的社区。此外,FimH 还促进了以下能力:
UPEC 将在胃肠道中建立一个储库,从那里他们可以通过尿道周围上升来传播尿路感染
区域进入膀胱。虽然 UPEC 存在遗传变异,但 FimH 是核心大肠杆菌基因组的一部分,尽管
已发现罕见菌株的 1 型操纵子发生突变。 FimH 免疫可预防
FDA 已允许在小鼠和猴膀胱炎模型中使用 UPEC UTI 和基于 FimH 的疫苗
患有多重耐药 UPEC 的患者。在动物模型中,保护是抗体介导的,如 FimH-
在受保护动物的尿液中发现了特异性 IgG 抗体,可以通过被动方式预防尿路感染
转移。有趣的是,在出现症状性尿路感染时,肠道中的 UPEC 丰度会增加,这表明
肠道定植是 rUTI 循环中的关键步骤。此外,该提案中的研究表明,引起粘膜
针对 FimH 的抗体反应可以减少 UPEC 在肠道的定植。鉴于这些发现,本提案
提出了抗 FimH 诱导抗体可以通过两种不同机制对抗 rUTI 的假设:i)
防止 UPEC 与尿路上皮结合; ii) 干扰 UPEC 在 GIT 上的定植,从而
降低 UPEC 进入尿路的可能性。该提案的目的是: i) 确定
针对 FimCH 的粘膜疫苗接种如何减少 UPEC 肠道定植(目标 1); ii) 利用疫苗诱导 B
细胞反应以分离 FimH 的单克隆抗体 (mAb) 并确定其表位特异性(目标 2);
iii) 在胃肠道定植和膀胱炎小鼠模型中使用这些单克隆抗体,以阐明其机制
保护(目标 3)。该研究计划将揭示抗 FimH 抗体发挥作用的机制
通过直接阻断膀胱结合和间接干扰 UPEC GIT 定植来预防尿路感染。
这些结果将为合理靶向影响数百万 rUTI 患者的尿路病原体提供信息。在
此外,我们的方法能够快速生成可用于治疗的抗 UPEC 人类单克隆抗体
和诊断。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Andrew Leon Kau其他文献
Andrew Leon Kau的其他文献
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{{ truncateString('Andrew Leon Kau', 18)}}的其他基金
Breathprinting as a window into gut microbiome chemoecology
呼吸印迹是了解肠道微生物组化学生态学的窗口
- 批准号:
10512356 - 财政年份:2022
- 资助金额:
$ 63.03万 - 项目类别:
Harnessing Antibody Responses to Prevent and Treat Urinary Tract Infections
利用抗体反应预防和治疗尿路感染
- 批准号:
10523527 - 财政年份:2021
- 资助金额:
$ 63.03万 - 项目类别:
Microbial Origin of Breath Volatile Metabolites
呼吸挥发性代谢物的微生物来源
- 批准号:
10171781 - 财政年份:2020
- 资助金额:
$ 63.03万 - 项目类别:
Microbial Origin of Breath Volatile Metabolites
呼吸挥发性代谢物的微生物来源
- 批准号:
10043038 - 财政年份:2020
- 资助金额:
$ 63.03万 - 项目类别:
THE MICROBIOTA AND MUCOSAL IMMUNE RESPONSES IN THE DEVELOPMENT OF ASTHMA
哮喘发生过程中的微生物群和粘膜免疫反应
- 批准号:
9211283 - 财政年份:2015
- 资助金额:
$ 63.03万 - 项目类别:
The human gut microbiome, malnutrition and vaccine responses
人类肠道微生物组、营养不良和疫苗反应
- 批准号:
8309675 - 财政年份:2011
- 资助金额:
$ 63.03万 - 项目类别:
The human gut microbiome, malnutrition and vaccine responses
人类肠道微生物组、营养不良和疫苗反应
- 批准号:
8469030 - 财政年份:2011
- 资助金额:
$ 63.03万 - 项目类别:
The human gut microbiome, malnutrition and vaccine responses
人类肠道微生物组、营养不良和疫苗反应
- 批准号:
8127100 - 财政年份:2011
- 资助金额:
$ 63.03万 - 项目类别:
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