The roles of Lyme spirochete adhesins in hematogenous dissemination
莱姆病螺旋体粘附素在血行传播中的作用
基本信息
- 批准号:10570186
- 负责人:
- 金额:$ 71.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-10 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AdhesivesAnimalsArthritisBacteriaBacterial AdhesinsBindingBiochemicalBiologyBlood VesselsBorrelia afzeliiBorrelia burgdorferiBorrelia gariniiCCL2 geneCell LineCellsChemosensitizationComplexDBL OncoproteinEndothelial CellsEndotheliumEventExtracellular MatrixGene FamilyGenerationsGenesGenetic TranscriptionGeographyHealth systemHematogenousHourInfectionInfectious Skin DiseasesIntegrin BindingInterleukin-10IntravenousInvadedInvestigationJointsLaboratoriesLeftLigandsLyme DiseaseMeasuresMediatingModelingMonitorMusNatureOrder SpirochaetalesOrganismOspC proteinPhasePreventionPrincipal InvestigatorProcessProtein ArrayResearch PersonnelRoleSkinTNF geneTestingTimeTissuesVector-transmitted infectious diseaseVisualizationchronic infectioncytokinedecorin binding protein Bgenetic analysisgenome wide screenin vivoinhibitorinsightintravital microscopymeetingsmicrobial colonizationmigrationmouse modelmutantneutrophilnovelpathogenic microbetick bitetransmission processvector tickvirtual
项目摘要
Upon transmission by a vector tick bite, Lyme disease spirochetes, primarily B. burgdorferi (Bb) in the US,
establish a local skin infection, then disseminate to multiple tissues. Chronic infection by Bb is often associated
with arthritis. Our laboratories have identified and/or characterized many Bb cell- or extracellular matrix (ECM)-
binding adhesins using multiple approaches, overcoming the challenges of defining their roles in Bb biology.
Our approaches include analyses of biochemical activities and generation of targeted mutants selectively
defective for a single adhesive activity and analysis of the mutants in multiple murine infection models. To gain
detailed mechanistic insight into interactions that may occur during Bb dissemination in vivo, following
intravenous inoculation we used intravital microscopy to characterize vascular attachment and transmigration
in skin and joint-proximal tissue. These studies revealed that adhesins BBK32 and VlsE account for virtually all
of the transient Bb-endothelium binding occurring minutes after inoculation, termed “Meeting” interactions. A
distinct set of adhesins, DbpB/A, OspC, and P66, mediate contacts required for invasion into extravascular
joint space after 24 hours (hr), termed “Transmigrating” interactions. Using isogenic strain sets that have
acquired or lost specific adhesive activities in multiple short-term and long-term infection models we showed
roles for five of the six Meeting or Transmigrating adhesins in short-term tissue localization and/or long-term
colonization in other murine infection models. While Transmigrating adhesins do not promote “Meeting”
interactions, our discovery of enhanced adhesive capacity of the endothelium as infection progresses has
helped clarify why different adhesins have roles at different stages of infection. Within hr, “Endothelial
Activation” permits BBK32- and VlsE-independent (“Greeting”) interactions. After ~24 hr “Endothelial
Potentiation” occurs, reflected by the ability of the joint vasculature to support Bb transmigration. Although both
OspC and P66 function as Transmigrating adhesins, only P66, an integrin-binding adhesin that alters
transcription in cultured endothelial cells, is also Potentiating, i.e., required to promote the rapid transmigration
of a second Bb strain. Activation is mimicked by exogenous treatment of mice with several cytokines produced
by infected mice, but potentiation is seen only with TNF-α, MCP-1 or IL-10. These findings reveal previously
unrecognized steps that are critical for Bb spread and provide a means to distinguish roles for each adhesin in
distinct infection stages: Meeting, Greeting, Potentiating, Transmigrating and Colonizing. In Aim 1 we will
identify known adhesins that facilitate Greeting interactions; to better prioritize our adhesin list, we propose a
genome-wide screen that may also identify novel adhesins. In Aim 2 we will clarify the roles of known (and, if
applicable, novel) adhesins in endothelial Potentiation and Transmigration. Our use of rigorous genetic
analyses in infection models from visualization of key interactions in vivo to quantitative analysis of Bb at
different stages of infection will result in detailed understanding of a critical facet of Bb biology: dissemination.
经蜱叮咬传播后,莱姆病螺旋体,在美国主要是伯氏疏螺旋体(Bb),
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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George Chaconas其他文献
George Chaconas的其他文献
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{{ truncateString('George Chaconas', 18)}}的其他基金
The roles of Lyme spirochete adhesins in hematogenous dissemination
莱姆病螺旋体粘附素在血行传播中的作用
- 批准号:
10464639 - 财政年份:2022
- 资助金额:
$ 71.46万 - 项目类别:
Functional Analyses of Borrelia burgdorferi Adhesins
伯氏疏螺旋体粘附素的功能分析
- 批准号:
9402006 - 财政年份:2016
- 资助金额:
$ 71.46万 - 项目类别:
Comprehensive Analysis of Borrelia burgdorferi Adhesins
伯氏疏螺旋体粘附素的综合分析
- 批准号:
8063374 - 财政年份:2011
- 资助金额:
$ 71.46万 - 项目类别:
Comprehensive Analysis of Borrelia burgdorferi Adhesins
伯氏疏螺旋体粘附素的综合分析
- 批准号:
8417758 - 财政年份:2011
- 资助金额:
$ 71.46万 - 项目类别:
Comprehensive Analysis of Borrelia burgdorferi Adhesins
伯氏疏螺旋体粘附素的综合分析
- 批准号:
8602821 - 财政年份:2011
- 资助金额:
$ 71.46万 - 项目类别:
Comprehensive Analysis of Borrelia burgdorferi Adhesins
伯氏疏螺旋体粘附素的综合分析
- 批准号:
8209007 - 财政年份:2011
- 资助金额:
$ 71.46万 - 项目类别:
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