Mechanisms of Leptospira interrogans interactions with the vascular endothelium in vivo
问号钩端螺旋体与体内血管内皮相互作用的机制
基本信息
- 批准号:10208696
- 负责人:
- 金额:$ 23.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-02 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAcuteAddressAdherenceAdherens JunctionAdhesionsAdhesivesAffectAnimalsBacteriaBacterial AdhesinsBindingBloodBlood VesselsBorreliaBorrelia burgdorferiC3H/HeJ MouseCell Surface ReceptorsCell surfaceCellsChronicClinicalCollectionCommunicable DiseasesComplementComplexCytoskeletonDataDevelopmentDiseaseDoseDrug or chemical Tissue DistributionEndothelial CellsEndotheliumEndotoxinsEnvironmentExposure toExtracellular MatrixFemaleGenomeHemorrhageHumanImpairmentIn VitroInfectionIntercellular JunctionsIntravenousInvadedKidney FailureLeptospiraLeptospira interrogansLeptospirosisLifeLipopolysaccharidesLiquid substanceLiver DysfunctionLivestockLungMaintenanceMinorModelingMouse StrainsMucous MembraneMultiple Organ FailureMusMutationOrder SpirochaetalesPathogenesisPathogenicityProteinsProximal Kidney TubulesRecombinantsRoleSeveritiesSiteSkinSlumSoilSourceTLR4 geneTestingTimeTissuesTreponemaUrineUrsidae FamilyVascular EndotheliumVascular PermeabilitiesWaterWorkZoonosesburden of illnesscadherin 5companion animalgain of functionin vivoinsightmalemembermouse modelmutantpathogenreceptor
项目摘要
Abstract
Leptospirosis is the most widespread zoonotic disease worldwide, and continues to emerge as a
significant infectious disease in urban slums, particularly in tropical regions. Several species of the
genus Leptospira can cause infection, which varies in severity from mild illness to fatal hemorrhagic
disease with multiple organ failure. Typically, infection of a maintenance (reservoir) host is chronic and
asymptomatic. Yet, the same bacterium can cause acute, potentially life-threatening infection in an
accidental host species. Persistence of leptospires in wildlife, companion animals, and livestock
provides a constant reservoir for human infection, as infected animals harbor Leptospira in the proximal
tubules of the kidney and excrete Leptospira in the urine. Release of viable bacteria into the
environment provides opportunities for infection of new hosts. Infection is acquired through exposure to
animal bodily fluids, especially urine, or from environmental sources contaminated with urine. Entry is
typically through mucous membranes or minor breaches in the skin, followed by dissemination to
multiple sites. Widespread endothelial damage is a prominent feature of leptospirosis.
Despite the global burden of disease, the pathogenic mechanisms of Leptospira species are
understudied. Adhesion to host molecules is critical to the abilities of many pathogens to establish
infection and cause disease, and is likely true for Leptospira, as well. Adhesion to host cell surface
molecules may facilitate invasion of tissues, but to date this question has not been mechanistically
addressed. While several candidate adhesive proteins have been identified, how these activities
contribute to pathogenicity in vivo remains unknown.
We demonstrated that the major contributor to endothelial cell-cell junctions, VE-cadherin, is a receptor
for L. interrogans. We also identified two adhesins that bind to VE-cadherin, demonstrated that L.
interrogans and purified recombinant adhesins cause disruption of adherens junctions, which are
critical to maintenance of endothelial integrity. In our work on another spirochete, Borrelia burgdorferi,
we developed a short-term intravenous inoculation model to determine the roles of B. burgdorferi
proteins in interactions with the vasculature in different tissue sites in living mice. In this
exploratory/developmental project, we will test the hypothesis that specific L. interrogans proteins
contribute to bacterial interaction with the endothelium in vivo. In Aim 1 we will test the hypothesis that
L. interrogans interacts with the vascular endothelium in living animals, and in Aim 2 we will test the
hypothesis that specific L. interrogans proteins that adhere to VE-cadherin in vitro have roles in
adherence of the bacteria to the endothelium in vivo. This exploratory/developmental work will refine
the mechanism by which three L. interrogans adhesins contribute to the pathogenesis of leptospirosis.
抽象的
钩端螺旋体病是世界范围内最普遍的人畜共患疾病,并且继续作为一种
城市贫民窟,特别是热带地区的重大传染病。几个品种的
钩端螺旋体属可引起感染,感染的严重程度从轻微疾病到致命的出血性感染不等
多器官功能衰竭的疾病。通常,维持(储存)宿主的感染是慢性的并且
无症状。然而,同一种细菌可能会导致急性、可能危及生命的感染。
偶然的宿主物种。钩端螺旋体在野生动物、伴侣动物和牲畜中的持久存在
为人类感染提供了一个恒定的储存库,因为受感染的动物在近端含有钩端螺旋体
肾小管并通过尿液排出钩端螺旋体。将活细菌释放到
环境为新宿主的感染提供了机会。感染是通过接触
动物体液,尤其是尿液,或来自被尿液污染的环境来源。条目是
通常通过粘膜或皮肤的微小裂口传播,然后传播到
多个站点。广泛的内皮损伤是钩端螺旋体病的一个显着特征。
尽管存在全球疾病负担,但钩端螺旋体物种的致病机制仍不清楚
待研究。对宿主分子的粘附对于许多病原体建立宿主的能力至关重要
感染并引起疾病,钩端螺旋体也可能如此。粘附于宿主细胞表面
分子可能会促进组织的侵袭,但迄今为止这个问题还没有从机制上得到解决
已解决。虽然已经鉴定了几种候选粘附蛋白,但这些活性如何
其体内致病性的贡献尚不清楚。
我们证明了内皮细胞与细胞连接的主要贡献者 VE-钙粘蛋白是一种受体
对于问号钩端螺旋体。我们还鉴定了两种与 VE-钙粘蛋白结合的粘附素,证明了 L.
问号和纯化的重组粘附素会破坏粘附连接,这是
对维持内皮完整性至关重要。在我们对另一种螺旋体伯氏疏螺旋体的研究中,
我们开发了一种短期静脉接种模型来确定伯氏疏螺旋体的作用
蛋白质与活体小鼠不同组织部位的脉管系统相互作用。在这个
探索/开发项目,我们将测试特定问号钩体蛋白的假设
有助于细菌与体内内皮细胞的相互作用。在目标 1 中,我们将检验以下假设:
问号钩端螺旋体与活体动物的血管内皮相互作用,在目标 2 中,我们将测试
假设体外粘附 VE-钙粘蛋白的特定问号问号蛋白在
细菌在体内粘附于内皮。这项探索性/开发性工作将完善
三种问号钩端螺旋体粘附素促进钩端螺旋体病发病机制的机制。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Hematogenous dissemination of pathogenic and non-pathogenic Leptospira in a short-term murine model of infection.
短期鼠感染模型中致病性和非致病性钩端螺旋体的血行传播。
- DOI:
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Surdel, Matthew C;Anderson, Phillip N;Hahn, Beth L;Coburn, Jenifer
- 通讯作者:Coburn, Jenifer
Heterologous production of the adhesin LIC13411 from pathogenic Leptospira facilitates binding of non-pathogenic Leptospira in vitro and in vivo.
从致病性钩端螺旋体异源产生粘附素 LIC13411 有助于非致病性钩端螺旋体在体外和体内的结合。
- DOI:
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Surdel, Matthew C;Hahn, Beth L;Anderson, Phillip N;Coburn, Jenifer
- 通讯作者:Coburn, Jenifer
Pathogenesis insights from an ancient and ubiquitous spirochete.
来自古老且普遍存在的螺旋体的发病机制见解。
- DOI:
- 发表时间:2021-10
- 期刊:
- 影响因子:6.7
- 作者:Coburn, Jenifer;Picardeau, Mathieu;Woods, Christopher W;Veldman, Timothy;Haake, David A
- 通讯作者:Haake, David A
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Jenifer L Coburn其他文献
Jenifer L Coburn的其他文献
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{{ truncateString('Jenifer L Coburn', 18)}}的其他基金
Genetic Approaches to Evaluation of the Roles of Leptospira interrogans Adhesins in Endothelial Interactions
评估问号钩端螺旋体粘附素在内皮相互作用中作用的遗传学方法
- 批准号:
10389686 - 财政年份:2022
- 资助金额:
$ 23.7万 - 项目类别:
Genetic Approaches to Evaluation of the Roles of Leptospira interrogans Adhesins in Endothelial Interactions
评估问号钩端螺旋体粘附素在内皮相互作用中作用的遗传学方法
- 批准号:
10612825 - 财政年份:2022
- 资助金额:
$ 23.7万 - 项目类别:
Investigation of the Porin Function of B. burgdorferi P66
伯氏疏螺旋体 P66 孔蛋白功能的研究
- 批准号:
9891001 - 财政年份:2019
- 资助金额:
$ 23.7万 - 项目类别:
Investigation of the Porin Function of B. burgdorferi P66
伯氏疏螺旋体 P66 孔蛋白功能的研究
- 批准号:
9762522 - 财政年份:2019
- 资助金额:
$ 23.7万 - 项目类别:
Identification of protective Lyme disease antigens using live attenuated vaccines
使用减毒活疫苗鉴定保护性莱姆病抗原
- 批准号:
9275338 - 财政年份:2016
- 资助金额:
$ 23.7万 - 项目类别:
Identification of protective Lyme disease antigens using live attenuated vaccines
使用减毒活疫苗鉴定保护性莱姆病抗原
- 批准号:
9917694 - 财政年份:2016
- 资助金额:
$ 23.7万 - 项目类别:
Multiple B. burgdorferi Factors Collaborate to Evade Complement-Mediated Defenses
多种伯氏疏螺旋体因子共同逃避补体介导的防御
- 批准号:
9187413 - 财政年份:2015
- 资助金额:
$ 23.7万 - 项目类别:
Leptospira interrogans Interactions with Endothelial Cells
问号钩端螺旋体与内皮细胞的相互作用
- 批准号:
8917853 - 财政年份:2014
- 资助金额:
$ 23.7万 - 项目类别:
Adhesion of Leptospira interrogans to the Renal Proximal Tubule
问号钩端螺旋体对肾近端小管的粘附
- 批准号:
8758246 - 财政年份:2014
- 资助金额:
$ 23.7万 - 项目类别:
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