Molecular basis of Wnt activation by Ehrlichia Wnt ligand mimics

埃里希体Wnt配体模拟物激活Wnt的分子基础

基本信息

  • 批准号:
    10117073
  • 负责人:
  • 金额:
    $ 19.34万
  • 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:
    2020-03-01 至 2023-02-28
  • 项目状态:
    已结题

项目摘要

Project Summary Ehrlichia chaffeensis (E. ch.) is a gram-negative, obligately intracellular bacterium and causative agent of the most prevalent life-threatening tick-borne disease in the United States, human monocytic ehrlichiosis (HME). Wnt signaling is a conserved eukaryotic signal cascade comprising canonical and noncanonical pathways that regulate events including cell fate, development, and cell polarity, as well as innate immunity-associated events such as autophagy, cytokine expression, and phagocytosis. Our laboratory has shown that during infection, E. ch. activates conserved eukaryotic signaling pathways including both canonical and noncanonical Wnt signaling. Wnt signaling enhances E. ch. intracellular survival by driving bacterial uptake and inhibiting fusion of the ehrlichial replicative vacuole with the lysosome. Although these studies have identified Wnt pathway activation as a virulence strategy for E. ch., identification of an activating event for the observed phenomena remains a critical gap in knowledge. Under normal physiological conditions, Wnt signaling- dependent phagocytosis is initiated through the binding of a Wnt ligand to one of 10 Frizzled (Fzd). Our preliminary data demonstrates that E. ch. surface protein TRP120 directly binds a Fzd, possesses homology with the conserved family of Wnt proteins, and can stimulate activation of the Wnt transcription factor β- catenin. We have also shown that inhibition of Wnt signaling blocks ehrlichial entry, indicating E. ch. effectively establishes infection through activation of Wnt-dependent phagocytosis. The long-term goal of this project is to utilize E. ch. manipulation of monocyte Wnt signaling as a model to study the therapeutic potential of harnessing Wnt signaling during human intracellular bacterial infection. The objective of this proposal is to define the bacterial ligand and eukaryotic receptor determinants of E. ch. effector-driven activation of Wnt signaling and entry into monocytes. We hypothesize that ehrlichial TRPs are Wnt ligand mimetics that signal through Wnt pathway receptor-coreceptor pairs for activation of canonical and noncanonical Wnt signaling to enhance bacterial host cell entry and intracellular survival. In specific aim 1, we will investigate ehrlichial TRP Wnt ligand mimetic activation of canonical and noncanonical Wnt signaling. In specific aim 2, we will define the role of Wnt pathway receptors and coreceptors in ehrlichial TRP-driven Wnt signaling activation during infection. This research will provide insight to evolutionarily conserved eukaryotic pathways that pathogens have evolved to utilize for cell invasion and intracellular growth. Our approach to identifying a level at which Wnt signaling can be hijacked by intracellular pathogens will provide mechanisms for previously observed phenomena as well as potential antimicrobial therapeutic targets
项目总结

项目成果

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JERE W MCBRIDE其他文献

JERE W MCBRIDE的其他文献

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{{ truncateString('JERE W MCBRIDE', 18)}}的其他基金

Ehrlichia Notch SLiM-activated oncoprotein inhibition of apoptosis
埃里希氏菌Notch SLiM激活的癌蛋白抑制细胞凋亡
  • 批准号:
    10365541
  • 财政年份:
    2021
  • 资助金额:
    $ 19.34万
  • 项目类别:
Ehrlichia Notch SLiM-activated oncoprotein inhibition of apoptosis
埃里希氏菌Notch SLiM激活的癌蛋白抑制细胞凋亡
  • 批准号:
    10513824
  • 财政年份:
    2021
  • 资助金额:
    $ 19.34万
  • 项目类别:
Ehrlichia TRP120 HECT E3 ubiquitin ligase modulation of host cell pathways
埃里希体 TRP120 HECT E3 泛素连接酶对宿主细胞途径的调节
  • 批准号:
    10248423
  • 财政年份:
    2020
  • 资助金额:
    $ 19.34万
  • 项目类别:
Ehrlichia TRP120 HECT E3 ubiquitin ligase modulation of host cell pathways
埃里希体 TRP120 HECT E3 泛素连接酶对宿主细胞途径的调节
  • 批准号:
    9975529
  • 财政年份:
    2020
  • 资助金额:
    $ 19.34万
  • 项目类别:
Notch signaling and functional relevance during Ehrlichia chaffeensis infection
恰菲埃里希体感染期间的Notch信号传导和功能相关性
  • 批准号:
    9408616
  • 财政年份:
    2017
  • 资助金额:
    $ 19.34万
  • 项目类别:
Notch signaling and functional relevance during Ehrlichia chaffeensis infection
恰菲埃里希体感染期间的Notch信号传导和功能相关性
  • 批准号:
    9316270
  • 财政年份:
    2017
  • 资助金额:
    $ 19.34万
  • 项目类别:
Wnt signaling during Ehrlichia infection
埃里希体感染期间的 Wnt 信号传导
  • 批准号:
    9167858
  • 财政年份:
    2016
  • 资助金额:
    $ 19.34万
  • 项目类别:
Rickettsiales: Disease Models, Immunity and Vaccine Development
立克次体:疾病模型、免疫和疫苗开发
  • 批准号:
    8911515
  • 财政年份:
    2015
  • 资助金额:
    $ 19.34万
  • 项目类别:
Ehrlichia modulation of polycomb group-dependent epigenetic regulation
埃里希体对多梳群依赖的表观遗传调控的调节
  • 批准号:
    8809777
  • 财政年份:
    2014
  • 资助金额:
    $ 19.34万
  • 项目类别:
Ehrlichia T1S Effector Regulation of Host Gene Transcription
埃里希体 T1S 宿主基因转录的效应调节
  • 批准号:
    8824870
  • 财政年份:
    2014
  • 资助金额:
    $ 19.34万
  • 项目类别:

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  • 批准号:
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  • 批准号:
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    03670243
  • 财政年份:
    1991
  • 资助金额:
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  • 项目类别:
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