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):金黄色葡萄球菌是在医院和社区环境中引起感染的最重要的人类病原体之一。由于高度的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,有一个重要的需要开发有效的治疗这种有机体。金黄色葡萄球菌致病成功的关键是

项目成果

期刊论文数量(0)
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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
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
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
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:
    10221497
  • 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:
    9976440
  • 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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