Mechanistic Studies Of The Mode Of Action Of The Staphylococcus aureus LukAB Cyto

金黄色葡萄球菌 LukAB Cyto 作用方式的机制研究

基本信息

项目摘要

DESCRIPTION (provided by applicant): Staphylococcus aureus is one of the most important human pathogens responsible for infections in both hospital and community settings. Therapeutic options to combat S. aureus infections are limited due to the high level of antibiotic resistance and lack of an effective vaccine. Thus, there is a significant need for the development of effective therapeutics against this organism. Critical to the pathogenic success of S. aureus is the ability of this bacterium to avoid clearance by the host via targeted killing of neutrophils; innate immune cells integral to the control of Staphylococcal infections. Thus, the long-term goal of this research program is to understand the mechanism employed by S. aureus to deplete these critical phagocytes. Recently, we have described the leukotoxin A/B (LukAB) as a virulence factor that plays an integral role in protecting S. aureus from neutrophil-mediated killing by targeting and eliminating these cells. In addition, we have demonstrated that LukAB contributes to the pathogenesis of community-associated, methicillin-resistant Staphylococcus aureus (CA-MRSA) in a murine model of systemic dissemination. We have found that: LukAB is conserved in S. aureus, contributes to the cytotoxicity of a variety of strains including methicilln-sensitive and methicillin- resistant S. aureus, is responsible for the killing of not only neutrophls, but also monocytes, macrophages and dendritic cells, is the most divergent member of the bi-component pore-forming family of toxins found in S. aureus, and it exhibits unique properties that have not been observed by the other leukotoxins. Based on our findings, we propose a model whereby LukAB selectively binds to phagocytes resulting in toxin oligomerization and pore-formation, which ultimately leads to membrane damage and killing of the target cell. The primary goal of this application is to test this model. To this end, we propose three Specific Aims. In Aim 1 we plan to elucidate the contribution of candidate cellular factors for LukAB tropism towards phagocytes. In Aim 2 we seek to define functional regions involved in LukAB-mediated toxicity. Lastly, in Aim 3 we propose to determine the mechanism by which LukAB contributes to S. aureus pathogenesis in vivo. To accomplish these Aims, we propose to employ a multidisciplinary approach that combines molecular biology, genetics, immunology, and biochemistry, together with ex vivo and in vivo infection models. Understanding the molecular details of how LukAB mediates targeting and killing of phagocytes is crucial for the development of novel therapeutic modalities to inhibit this toxin as a new approach to combat S. aureus infections.
描述(由申请人提供):金黄色葡萄球菌是导致医院和社区感染的最重要的人类病原体之一。由于高度抗生素耐药性和缺乏有效的疫苗,对抗金黄色葡萄球菌感染的治疗选择有限。因此,非常需要开发针对该生物体的有效疗法。金黄色葡萄球菌成功致病的关键是 该细菌通过靶向杀死中性粒细胞来避免被宿主清除的能力;先天免疫细胞对于控制葡萄球菌感染至关重要。因此,该研究计划的长期目标是了解金黄色葡萄球菌消耗这些关键吞噬细胞的机制。最近,我们将白细胞毒素 A/B (LukAB) 描述为一种毒力因子,通过靶向和消除这些细胞,在保护金黄色葡萄球菌免受中性粒细胞介导的杀伤方面发挥着不可或缺的作用。此外,我们还证明 LukAB 在全身传播的小鼠模型中有助于社区相关的耐甲氧西林金黄色葡萄球菌 (CA-MRSA) 的发病机制。我们发现: LukAB 在金黄色葡萄球菌中是保守的,有助于多种菌株(包括甲氧西林敏感和耐甲氧西林金黄色葡萄球菌)的细胞毒性,不仅负责杀死中性粒细胞,还负责杀死单核细胞、巨噬细胞和树突状细胞,是金黄色葡萄球菌中发现的双组分成孔毒素家族中最不同的成员, 它具有其他白细胞毒素未观察到的独特特性。根据我们的发现,我们提出了一个模型,通过该模型,LukAB 选择性地与吞噬细胞结合,导致毒素寡聚化和孔形成,最终导致膜损伤并杀死靶细胞。该应用程序的主要目标是测试该模型。为此,我们提出三个具体目标。在目标 1 中,我们计划阐明候选细胞因子对 LukAB 对吞噬细胞的趋向性的贡献。在目标 2 中,我们试图定义参与 LukAB 介导的毒性的功能区域。最后,在目标 3 中,我们建议确定 LukAB 在体内促进金黄色葡萄球菌发病的机制。为了实现这些目标,我们建议采用多学科方法,将分子生物学、遗传学、免疫学和生物化学与离体和体内感染模型结合起来。了解 LukAB 如何介导靶向和杀死吞噬细胞的分子细节对于开发抑制这种毒素的新型治疗方式至关重要,作为对抗金黄色葡萄球菌感染的新方法。

项目成果

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Victor J. Torres其他文献

How do we manage post-OLT redundant bile duct?
我们如何管理 OLT 后多余胆管?
  • DOI:
    10.3748/wjg.v19.i16.2501
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    4.3
  • 作者:
    Victor J. Torres;Nicholas Martinez;Gabriel H. Lee;J. Almeda;G. Gross;Sandeep N. Patel;L. Rosenkranz
  • 通讯作者:
    L. Rosenkranz
SARS-CoV-2 infection predisposes patients to coinfection with emStaphylococcus aureus/em
严重急性呼吸综合征冠状病毒 2 型感染使患者易并发金黄色葡萄球菌感染
  • DOI:
    10.1128/mbio.01667-24
  • 发表时间:
    2024-07-26
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Ashira Lubkin;Lucie Bernard-Raichon;Ashley L. DuMont;Ana Mayela Valero Jimenez;Gregory G. Putzel;Juan Gago;Erin E. Zwack;Olufolakemi Olusanya;Kristina M. Boguslawski;Simone Dallari;Sophie Dyzenhaus;Christin Herrmann;Juliana K. Ilmain;Georgia L. Isom;Miranda Pawline;Andrew I. Perault;Sofya Perelman;William E. Sause;Ifrah Shahi;Amelia St. John;Victor J. Torres
  • 通讯作者:
    Victor J. Torres
The two-component system WalKR provides an essential link between cell wall homeostasis and DNA replication in emStaphylococcus aureus/em
双组分系统 WalKR 在金黄色葡萄球菌中提供了细胞壁稳态与 DNA 复制之间的重要联系
  • DOI:
    10.1128/mbio.02262-23
  • 发表时间:
    2023-11-10
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Liam K. R. Sharkey;Romain Guerillot;Calum J. Walsh;Adrianna M. Turner;Jean Y. H. Lee;Stephanie L. Neville;Stephan Klatt;Sarah L. Baines;Sacha J. Pidot;Fernando J. Rossello;Torsten Seemann;Hamish E. G. McWilliam;Ellie Cho;Glen P. Carter;Benjamin P. Howden;Christopher A. McDevitt;Abderrahman Hachani;Timothy P. Stinear;Ian R. Monk;Victor J. Torres
  • 通讯作者:
    Victor J. Torres
Autophagy and microbial pathogenesis
自噬与微生物发病机制
  • DOI:
    10.1038/s41418-019-0481-8
  • 发表时间:
    2020-01-02
  • 期刊:
  • 影响因子:
    15.400
  • 作者:
    Matthew D. Keller;Victor J. Torres;Ken Cadwell
  • 通讯作者:
    Ken Cadwell
Modulation of emSalmonella/em virulence by a novel SPI-2 injectisome effector that interacts with the dystrophin-associated protein complex
一种与肌营养不良蛋白相关蛋白复合物相互作用的新型 SPI-2 注射体效应子对 emSalmonella/em 毒力的调节
  • DOI:
    10.1128/mbio.01128-24
  • 发表时间:
    2024-06-04
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Xiu-Jun Yu;Haixia Xie;Yan Li;Mei Liu;Ruhong Hou;Alexander V. Predeus;Blanca M. Perez Sepulveda;Jay C. D. Hinton;David W. Holden;Teresa L. M. Thurston;Victor J. Torres
  • 通讯作者:
    Victor J. Torres

Victor J. Torres的其他文献

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{{ truncateString('Victor J. Torres', 18)}}的其他基金

Investigating the relationship between antibiotics and nosocomial pneumonia.
调查抗生素与院内肺炎的关系。
  • 批准号:
    10078595
  • 财政年份:
    2020
  • 资助金额:
    $ 42.38万
  • 项目类别:
Alternatively activated macrophages during helminth infection
蠕虫感染期间巨噬细胞的选择性激活
  • 批准号:
    9976440
  • 财政年份:
    2017
  • 资助金额:
    $ 42.38万
  • 项目类别:
Alternatively activated macrophages during helminth infection
蠕虫感染期间巨噬细胞的选择性激活
  • 批准号:
    10221497
  • 财政年份:
    2017
  • 资助金额:
    $ 42.38万
  • 项目类别:
Contribution of LukED to Staphylococcus aureus pathobiology
LukED 对金黄色葡萄球菌病理学的贡献
  • 批准号:
    10893253
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:
Contribution of LukED to Staphylococcus aureus pathobiology
LukED 对金黄色葡萄球菌病理学的贡献
  • 批准号:
    8774582
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:
Mechanistic Studies Of The Mode Of Action Of The Staphylococcus aureus LukAB Cyto
金黄色葡萄球菌 LukAB Cyto 作用方式的机制研究
  • 批准号:
    8437950
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:
Contribution of LukED to Staphylococcus aureus pathobiology
LukED 对金黄色葡萄球菌病理学的贡献
  • 批准号:
    9978683
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:
Contribution of LukED to Staphylococcus aureus pathobiology
LukED 对金黄色葡萄球菌病理学的贡献
  • 批准号:
    10214497
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:
Contribution of LukED to Staphylococcus aureus pathobiology
LukED 对金黄色葡萄球菌病理学的贡献
  • 批准号:
    8632282
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:
Contribution of LukED to Staphylococcus aureus pathobiology
LukED 对金黄色葡萄球菌病理学的贡献
  • 批准号:
    10652464
  • 财政年份:
    2013
  • 资助金额:
    $ 42.38万
  • 项目类别:

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