Intravital assessment of Borrelia burgdorferi immune clearance in skin
皮肤伯氏疏螺旋体免疫清除率的活体评估
基本信息
- 批准号:9185801
- 负责人:
- 金额:$ 38.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-22 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAgonistAntibioticsAntibodiesAppearanceB-LymphocytesBacteriaBehaviorBindingBiological Response ModifiersBiteBorrelia burgdorferiCell CommunicationCellsCharacteristicsChronicConfocal MicroscopyDataDendritic CellsDevelopmentDiagnosisDiseaseEnvironmentEventExhibitsExtracellular MatrixFeedbackFluorescenceFour-dimensionalGenerationsGoalsHealth Care CostsImageImaging TechniquesImmuneImmune responseImmunotherapyIn SituIn VitroInfectionInfection preventionInflammatory ResponseInterleukin-10KineticsKnock-in MouseLabelLaboratoriesLifeLipoproteinsLongevityLyme DiseaseMeasuresMediatingMediator of activation proteinMethodsMicroscopyModelingMusNeutrophil InfiltrationNorth AmericaParasitesPhagocytesPhagocytosisPhasePlayPopulationPublic HealthPublishingRoleSkinSkin TissueStagingSurfaceSyringesSystemT-LymphocyteTechniquesTicksTimeTissuesVascular PermeabilitiesVector-transmitted infectious diseaseVirulenceadaptive immunitybasecell motilitycell typecytokineimmune clearanceimmune functionin vivoin vivo Modelintradermal injectionintravital imagingintravital microscopykillingsmacrophagemouse modelnovelpathogenpreventresponsetooltransmission process
项目摘要
Transmission of Borrelia burgdorferi (Bb) via tick-bite leads to the development of Lyme disease, which is the
leading vector-borne disease in North America. If not diagnosed and treated appropriately with antibiotics, Bb
can produce lasting and debilitating disease in myriad tissues, resulting in significant personal and public
health costs. After transmission into a host, the bacteria remain locally in the skin tissues for at least 12-48h
before disseminating via the skin to eventually establish persistent infection in multiple tissues throughout the
host. The mechanisms by which Bb evades immune clearance are largely unknown. In vitro analyses have
been shown to be lacking in their ability to accurately identify host responses to this unique obligate parasite,
highlighting the need for better in vivo models. Our group has recently developed novel intravital microscopy
techniques that allow for the direct assessment of fluorescent Bb with different immune cell populations directly
within the intact skin of living mice and in real-time, providing us for the first time with the tools to accurately
assess these critical interactions in the natural host environment. Preliminary data indicates these techniques
can accurately delineate depth and distance in skin tissues, identify different extracellular matrix molecules and
their co-localization with Bb, and distinguish/measure different diverse motility and interactive characteristics of
both Bb and key innate immune cell types, confirming that our techniques are able to perform these analyses.
The overall goal is to use these intravital techniques, together with established infection models, to more
accurately assess Bb interactions with important immune cell populations and mediators within host skin
tissues, and thus more accurately identify virulence mechanisms that are critical for escaping immune
clearance and causing Lyme disease. Our preliminary studies have delineated the population kinetics of Bb in
skin over >2 years, as well as identified Bb-elicited IL-10 as mediating suppressive effects on overall immune
functions and Bb clearance. Based on these findings, fluorescent Bb will be used to provide real-time
feedback to determine the relative importance of different immune mechanisms in controlling Bb numbers
within skin, different pools of fluorescently-labeled Bb-specific Ab will be used to delineate how Abs interact
with Bb during the acute phases of LD, and different IL-10-deficient mouse models utilized to determine how
IL-10 suppresses efficient clearance of Bb from mouse tissues. The specific aims for this proposal are:
Aim 1. Delineate the mechanisms for Bb-elicited IL-10-mediated suppression of innate immune responses to
Bb infection within skin tissues.
Aim 2. Delineate the mechanisms that inhibit Ab-mediated clearance of Bb.
These studies should provide the first accurate description of the Bb-immune cell interactions that occur during
natural infection and dissemination in skin tissues, and may identify targets for potential Lyme therapies.
伯氏疏螺旋体(Bb)通过蜱叮咬传播导致莱姆病的发展,莱姆病是莱姆病的主要病原体。
北美最主要的病媒传染疾病如果没有得到诊断和适当的抗生素治疗,
可以在无数组织中产生持久和使人衰弱的疾病,导致重大的个人和公共疾病。
医疗费用。在传播到宿主体内后,细菌在皮肤组织中局部保留至少12- 48小时
然后通过皮肤传播,最终在整个组织的多个组织中建立持续感染。
主持人Bb逃避免疫清除的机制在很大程度上是未知的。体外分析具有
已经证明它们缺乏准确识别宿主对这种独特的专性寄生虫的反应的能力,
突出了对更好的体内模型的需要。我们小组最近开发了一种新的活体显微镜
允许直接用不同免疫细胞群直接评估荧光Bb的技术
在活体小鼠的完整皮肤内,并实时地,为我们提供了第一次准确地
评估自然宿主环境中这些关键的相互作用。初步数据显示,这些技术
可以准确描绘皮肤组织中的深度和距离,识别不同的细胞外基质分子,
它们与Bb的共定位,并区分/测量不同的多样性运动和相互作用的特点,
Bb和关键的先天免疫细胞类型,证实我们的技术能够进行这些分析。
总体目标是使用这些活体技术,连同已建立的感染模型,
准确评估Bb与宿主皮肤内重要免疫细胞群和介质的相互作用
组织,从而更准确地识别对逃避免疫至关重要的毒力机制,
清除并导致莱姆病。我们的初步研究已经描绘了Bb的种群动力学,
皮肤>2年,以及确定的BB-引起的IL-10介导的总体免疫抑制作用
功能和Bb清除。基于这些发现,荧光Bb将用于提供实时
反馈以确定不同免疫机制在控制Bb数量中的相对重要性
在皮肤内,将使用不同的荧光标记的Bb特异性抗体池来描述抗体如何相互作用
在LD的急性期与Bb,以及不同的IL-10缺陷小鼠模型用于确定如何
IL-10抑制Bb从小鼠组织的有效清除。这项建议的具体目标是:
目标1。阐明BB诱导的IL-10介导的先天性免疫应答抑制的机制,
皮肤组织内的血吸虫感染。
目标二。阐明抑制Ab介导的Bb清除的机制。
这些研究应该提供第一个准确的描述BB-免疫细胞相互作用发生在
自然感染和皮肤组织中的传播,并可能确定潜在的莱姆病治疗的目标。
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)
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RONALD MARK WOOTEN其他文献
RONALD MARK WOOTEN的其他文献
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{{ truncateString('RONALD MARK WOOTEN', 18)}}的其他基金
Intravital assessment of Borrelia burgdorferi-immune cell interactions in skin
皮肤中伯氏疏螺旋体与免疫细胞相互作用的活体评估
- 批准号:
8898321 - 财政年份:2014
- 资助金额:
$ 38.97万 - 项目类别:
Dysregulation of Innate Immune Responses by Borrelia burgdorferi:A Role for IL-10
伯氏疏螺旋体引起的先天免疫反应失调:IL-10 的作用
- 批准号:
7527261 - 财政年份:2008
- 资助金额:
$ 38.97万 - 项目类别:
Dysregulation of Innate Immune Responses by Borrelia burgdorferi:A Role for IL-10
伯氏疏螺旋体引起的先天免疫反应失调:IL-10 的作用
- 批准号:
7624969 - 财政年份:2008
- 资助金额:
$ 38.97万 - 项目类别:
Dysregulation of Innate Immune Responses by Borrelia burgdorferi:A Role for IL-10
伯氏疏螺旋体引起的先天免疫反应失调:IL-10 的作用
- 批准号:
8074068 - 财政年份:2008
- 资助金额:
$ 38.97万 - 项目类别:
Dysregulation of Innate Immune Responses by Borrelia burgdorferi:A Role for IL-10
伯氏疏螺旋体引起的先天免疫反应失调:IL-10 的作用
- 批准号:
7848334 - 财政年份:2008
- 资助金额:
$ 38.97万 - 项目类别:
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