New approaches to Study Pseudomonas-host interactions

研究假单胞菌与宿主相互作用的新方法

基本信息

项目摘要

DESCRIPTION (provided by applicant): The ability of microbial pathogens to overcome the normally highly polarized host mucosal epithelial barrier is an early and critical step in pathogenesis. This is particularly critical for opportunistic pathogens such as Pseudomonas aeruginosa (PA), one of the most virulent opportunistic pathogens of man. In the setting of epithelial injury and loss of cell polarity, however, PA can effectively colonize the mucosal surfaces and cause further damage, prevent repair of the wounded epithelium, and disseminate. Our long term goals are to understand how pathogens in general, and PA in particular, overcome the host epithelial barrier to cause human disease. Our short term goals are to understand how PA hijacks host signaling pathways to enter into cells and how disruption of cell polarity predisposes to PA invasion. We have used a novel forward genetic approach, genome-wide RNAi-mediated gene inactivation, to carry out a targeted genetic screen to identify host proteins important for bacterial binding and internalization. From this screen, we have identified many new host genes required for entry of strain PAK, including a putative receptor (E-cadherin), adaptor proteins (Abl/arg kinase and Crk), regulators of the cytoskeleton (Cdc42, Rac, and p21-activated protein kinase (Pak)), and downstream effectors (phosphoinositol-3-phospho kinase (PI3K) and Akt). We are uniquely poised now to determine how these host molecules are subverted by PA when it enters mammalian cells and whether it is relevant to human disease. These studies, which employ novel genetic approaches and state-of-the-art cell biology, will comprehensively dissect the interactions between PA and host cell epithelium. They will identify host factors that the bacteria exploit to cause disease. These host cell factors may serve as novel targets for the development of anti-bacterial therapeutics; because the drug targets host but not bacterial molecules, they are much less likely to engender resistance compared to conventional anti-microbial therapies.
描述(由申请人提供):微生物病原体克服通常高度极化的宿主粘膜上皮屏障的能力是发病机制的早期和关键步骤。这对铜绿假单胞菌(PA)等机会致病菌尤其重要,这是人类最致命的机会致病菌之一。然而,在上皮损伤和细胞极性丧失的情况下,PA可以有效地定殖在粘膜表面,造成进一步的损伤,阻止损伤上皮的修复,并传播。我们的长期目标是了解一般的病原体,特别是PA如何克服宿主上皮屏障导致人类疾病。我们的短期目标是了解PA是如何劫持宿主信号通路进入细胞的,以及细胞极性的破坏是如何导致PA入侵的。我们使用了一种新的正向遗传方法,全基因组rnai介导的基因失活,来进行靶向遗传筛选,以鉴定对细菌结合和内化重要的宿主蛋白。从这个筛选中,我们已经确定了许多菌株PAK进入所需的新宿主基因,包括假定的受体(E-cadherin),适配器蛋白(Abl/arg激酶和Crk),细胞骨架调节因子(Cdc42, Rac和p21活化蛋白激酶(PAK))和下游效应物(磷酸肌醇-3-磷酸激酶(PI3K)和Akt)。我们现在可以确定PA进入哺乳动物细胞时这些宿主分子是如何被破坏的,以及它是否与人类疾病有关。这些研究采用新颖的遗传方法和最先进的细胞生物学,将全面剖析PA和宿主细胞上皮之间的相互作用。他们将确定细菌利用的致病宿主因素。这些宿主细胞因子可能成为开发抗菌药物的新靶点;由于这种药物针对的是宿主而不是细菌分子,因此与传统的抗微生物疗法相比,它们产生耐药性的可能性要小得多。

项目成果

期刊论文数量(0)
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Joanne N. Engel其他文献

Inhibition of the in vitro pituitary response to luteinizing hormone-releasing hormone by melatonin, serotonin, and 5-methoxytryptamine.
褪黑激素、血清素和 5-甲氧基色胺抑制体外垂体对黄体生成素释放激素的反应。
  • DOI:
    10.1210/endo-100-3-675
  • 发表时间:
    1977
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Jeanne E. Martin;Joanne N. Engel;David C. Klein
  • 通讯作者:
    David C. Klein
Global mapping of the Chlamydia trachomatis conventional secreted effector – host interactome reveals CebN interacts with nucleoporins and Rae1 to impede STAT1 nuclear translocation
沙眼衣原体常规分泌效应子-宿主相互作用组的全局图谱揭示 CebN 与核孔蛋白和 Rae1 相互作用以阻止 STAT1 核转位
  • DOI:
    10.1101/2024.04.25.587017
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    0
  • 作者:
    B. Steiert;Shelby E Andersen;Paige N. McCaslin;C. Elwell;R. Faris;Xavier Tijerina;Parker Smith;Quinn Eldridge;Brian S. Imai;Justine V. Arrington;Peter M. Yau;Kathleen M. Mirrashidi;Jeffrey R. Johnson;Erik Verschueren;John Von Dollen;Gwendolyn M. Jang;N. Krogan;Joanne N. Engel;Mary M. Weber
  • 通讯作者:
    Mary M. Weber
The emChlamydia/em effector Dre1 binds dynactin to reposition host organelles during infection
衣原体效应蛋白 Dre1 与动力蛋白复合物结合,在感染过程中重新定位宿主细胞器
  • DOI:
    10.1016/j.celrep.2025.115509
  • 发表时间:
    2025-04-22
  • 期刊:
  • 影响因子:
    6.900
  • 作者:
    Jessica Sherry;Komal Ishwar Pawar;Lee Dolat;Erin Smith;I-Chang Chang;Khavong Pha;Robyn Kaake;Danielle L. Swaney;Clara Herrera;Eleanor McMahon;Robert J. Bastidas;Jeffrey R. Johnson;Raphael H. Valdivia;Nevan J. Krogan;Cherilyn A. Elwell;Kliment Verba;Joanne N. Engel
  • 通讯作者:
    Joanne N. Engel
Antagonistic response regulators spatially regulate receptor methylation in the emPseudomonas aeruginosa/em Pil-Chp surface sensing system
对抗性反应调节因子在铜绿假单胞菌 Pil-Chp 表面感应系统中对受体甲基化进行空间调节
  • DOI:
    10.1016/j.celrep.2025.115536
  • 发表时间:
    2025-04-22
  • 期刊:
  • 影响因子:
    6.900
  • 作者:
    Ramiro Patino;Marco J. Kühn;Henriette Macmillan;Yuki F. Inclan;Ivan Chavez;Alexandre Persat;Joanne N. Engel
  • 通讯作者:
    Joanne N. Engel

Joanne N. Engel的其他文献

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{{ truncateString('Joanne N. Engel', 18)}}的其他基金

Finding the way: Sensory adaptation during bacterial mechanotransduction
寻找方法:细菌机械传导过程中的感觉适应
  • 批准号:
    10744926
  • 财政年份:
    2023
  • 资助金额:
    $ 28.18万
  • 项目类别:
Dissecting the role of the Inclusion membrane protein IncE, a master multi-tasking scaffolding protein, in the pathogenesis of Chlamydia trachomatis infections
剖析包涵膜蛋白 IncE(一种主要的多任务支架蛋白)在沙眼衣原体感染发病机制中的作用
  • 批准号:
    10453533
  • 财政年份:
    2022
  • 资助金额:
    $ 28.18万
  • 项目类别:
Dissecting the role of the Inclusion membrane protein IncE, a master multi-tasking scaffolding protein, in the pathogenesis of Chlamydia trachomatis infections
剖析包涵膜蛋白 IncE(一种主要的多任务支架蛋白)在沙眼衣原体感染发病机制中的作用
  • 批准号:
    10669588
  • 财政年份:
    2022
  • 资助金额:
    $ 28.18万
  • 项目类别:
Sensing living P. aeruginosa using D-alanine derived radiotracers
使用 D-丙氨酸衍生的放射性示踪剂感测活的铜绿假单胞菌
  • 批准号:
    10230924
  • 财政年份:
    2021
  • 资助金额:
    $ 28.18万
  • 项目类别:
Sensing living P. aeruginosa using D-alanine derived radiotracers
使用 D-丙氨酸衍生的放射性示踪剂感测活的铜绿假单胞菌
  • 批准号:
    10399593
  • 财政年份:
    2021
  • 资助金额:
    $ 28.18万
  • 项目类别:
Sensing living P. aeruginosa using D-alanine derived radiotracers
使用 D-丙氨酸衍生的放射性示踪剂感测活的铜绿假单胞菌
  • 批准号:
    10570987
  • 财政年份:
    2021
  • 资助金额:
    $ 28.18万
  • 项目类别:
Inclusion membrane protein (Inc) modulation of the innate immune response to Chlamydia trachomatis
包涵膜蛋白 (Inc) 调节沙眼衣原体先天免疫反应
  • 批准号:
    10246668
  • 财政年份:
    2020
  • 资助金额:
    $ 28.18万
  • 项目类别:
Understanding the role of sensory adaptation in bacterial mechanochemical signaling pathways
了解感觉适应在细菌机械化学信号通路中的作用
  • 批准号:
    10204959
  • 财政年份:
    2020
  • 资助金额:
    $ 28.18万
  • 项目类别:
Adapting to a changing environment: How surface contact induces virulence factor production in Pseudomonas aeruginosa
适应不断变化的环境:表面接触如何诱导铜绿假单胞菌产生毒力因子
  • 批准号:
    9403170
  • 财政年份:
    2017
  • 资助金额:
    $ 28.18万
  • 项目类别:
Decoding the Chlamydia inclusion membrane protein-host protein interactome
解码衣原体包涵膜蛋白-宿主蛋白相互作用组
  • 批准号:
    9185266
  • 财政年份:
    2015
  • 资助金额:
    $ 28.18万
  • 项目类别:
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