Inhibition of Candida virulence and biofilm formation by a bacterial peptide

细菌肽抑制念珠菌毒力和生物膜形成

基本信息

项目摘要

PROJECT SUMMARY/ABSTRACT The medical condition oropharyngeal candidiasis (OPC) is a major source of oral morbidity in patient groups including the immunosuppressed (cancer and AIDS patients) and those taking broad-spectrum antibiotics. We recently identified a peptide produced by Enterococcus faecalis that inhibits the hyphal morphogenesis and biofilm formation of the primary causative agent of OPC, Candida albicans. The research proposed in this ap- plication seeks to understand how the mature form of this peptide, EntV, is generated, how it targets C. albi- cans hyphal morphogenesis, and the extent to which it protects against OPC, thereby filling a critical gap in our knowledge and providing new avenues for the development of therapeutics. The long-term goal of this re- search is to develop novel strategies for treating and preventing oropharyngeal candidiasis. The objective of this application is to determine the generation, mode of action and therapeutic potential of EntV. The central hypothesis is that secreted and processed EntV acts on signaling pathway(s) that controls hyphal development in C. albicans resulting in protection from candidiasis. The rationale for this research is that identification of the mechanism by which EntV inhibits the formation of the invasive form of C. albicans will lead to new treatment strategies. By pursing three aims, the objective of this application will be attained. Aim #1 will elucidate how the active form of EntV is generated. Using both genetic and biochemical approaches, we will test the hypothesis that the proteases GelE and/or SprE are required for cleavage, and disulfide bond formation is catalyzed by a DsbA homolog. In Aim #2, the genes/pathways of C. albicans that are targeted by E. faecalis to inhibit hyphal morphogenesis will be determined using cell biological and genetic approaches. Based on preliminary data, the working hypothesis is that EntV interacts directly with one of several known discrete subdomains on the C. albicans cell surface to disrupt cell-cell and cell-substrate adherence, both of which are essential for biofilm formation. The efficacy of EntV and related peptides in protecting against C. albicans infection will be tested in Aim #3. Tissue culture cells (macrophages and oral epithelial cells) and mouse models of OPC and gastroin- testinal colonization will be utilized. We postulate that EntV will protect against C. albicans infection and can- didiasis in the nanomolar range. The significance of this contribution will be the knowledge of how a bacterial peptide inhibits C. albicans hyphal morphogenesis, potentially opening new avenues for therapeutic design. Targeting hyphal morphogenesis as an area for the possible development of novel therapeutics is innovative, as current antifungals are directed against the integrity or growth of the cell envelope. Additional benefits of this research include new knowledge in the fields of bacterial peptide generation, fungal morphotype switching, and inter-kingdom microbial interactions.
项目总结/摘要 口咽念珠菌病(OPC)是口腔疾病的主要病因 包括免疫抑制者(癌症和艾滋病患者)和那些服用广谱抗生素的人。我们 最近鉴定了一种由粪肠球菌产生的肽,其抑制菌丝形态发生, OPC的主要病原体白色念珠菌的生物膜形成。本研究中提出的- 应用程序试图了解这种肽的成熟形式,EntV,是如何产生的,它如何靶向C。白色,白色 可以菌丝形态发生,以及它对OPC的保护程度,从而填补了我们的关键空白, 知识,并为治疗的发展提供新的途径。这一改革的长期目标是-- 研究旨在开发治疗和预防口咽念珠菌病的新策略。的目标 本申请旨在确定EntV的产生、作用方式和治疗潜力。中央 一种假说是分泌和加工的EntV作用于控制菌丝发育的信号通路 in C.白色念珠菌导致保护免受念珠菌病。这项研究的基本原理是, EntV抑制C.白色念珠菌将导致新的治疗方法 战略布局通过追求三个目标,将达到本申请的目的。目标1将阐明 生成EntV的活性形式。我们将使用遗传学和生物化学的方法来检验这一假设 蛋白酶GelE和/或SprE是切割所需的,并且二硫键的形成由蛋白酶GelE和/或SprE催化。 DsbA同系物。在目标#2中,C.白色念珠菌是E.粪菌抑制菌丝 将使用细胞生物学和遗传学方法来确定形态发生。根据初步数据, 工作假设是EntV直接与C上几个已知的离散亚结构域之一相互作用。 白念珠菌细胞表面破坏细胞-细胞和细胞-基质粘附,这两者都是生物膜所必需的 阵EntV及其相关肽在预防C.白色念珠菌感染将在 目标3。组织培养细胞(巨噬细胞和口腔上皮细胞)和OPC和胃蛋白酶的小鼠模型。 将利用肠定殖。我们假设EntV将保护免受C。白色念珠菌感染,可以- 纳摩尔范围内的双孢子虫病。这一贡献的重要性将是了解细菌如何 肽抑制C.白色念珠菌菌丝形态发生,潜在地为治疗设计开辟新途径。 将菌丝形态发生作为可能开发新疗法的领域是创新的, 因为目前的抗真菌剂针对细胞被膜的完整性或生长。这一点的额外好处 研究包括细菌肽生成,真菌形态转换, 微生物之间的相互作用

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Host-derived reactive oxygen species trigger activation of the Candida albicans transcription regulator Rtg1/3.
  • DOI:
    10.1371/journal.ppat.1011692
  • 发表时间:
    2023-09
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
  • 通讯作者:
The pathogenesis of cardiac microlesion formation during severe bacteremic infection.
  • DOI:
    10.1371/journal.ppat.1009021
  • 发表时间:
    2020-11
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
    Brown AO;Garsin DA
  • 通讯作者:
    Garsin DA
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Danielle A Garsin其他文献

Vertebrate and invertebrate animal infection models of emCandida auris/em pathogenicity
Candida auris(耳念珠菌)致病性的脊椎动物和无脊椎动物感染模型
  • DOI:
    10.1016/j.mib.2024.102506
  • 发表时间:
    2024-08-01
  • 期刊:
  • 影响因子:
    7.500
  • 作者:
    Melissa Martinez;Danielle A Garsin;Michael C Lorenz
  • 通讯作者:
    Michael C Lorenz

Danielle A Garsin的其他文献

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{{ truncateString('Danielle A Garsin', 18)}}的其他基金

Inhibition of Candida Virulence and Biofilm Formation by a Bacterial Peptide
细菌肽抑制念珠菌毒力和生物膜形成
  • 批准号:
    10302700
  • 财政年份:
    2021
  • 资助金额:
    $ 7.6万
  • 项目类别:
Ethanolamine utilizing bacterial microcompartments in host cells
乙醇胺利用宿主细胞中的细菌微区室
  • 批准号:
    10495242
  • 财政年份:
    2021
  • 资助金额:
    $ 7.6万
  • 项目类别:
Ethanolamine utilizing bacterial microcompartments in host cells
乙醇胺利用宿主细胞中的细菌微区室
  • 批准号:
    10385013
  • 财政年份:
    2021
  • 资助金额:
    $ 7.6万
  • 项目类别:
Response To Immune Associated Stress
对免疫相关应激的反应
  • 批准号:
    10709154
  • 财政年份:
    2020
  • 资助金额:
    $ 7.6万
  • 项目类别:
Response to Immune Associated Stress
对免疫相关应激的反应
  • 批准号:
    10348727
  • 财政年份:
    2020
  • 资助金额:
    $ 7.6万
  • 项目类别:
Response to Immune Associated Stress
对免疫相关应激的反应
  • 批准号:
    10574586
  • 财政年份:
    2020
  • 资助金额:
    $ 7.6万
  • 项目类别:
Response to Immune Associated Stress
对免疫相关应激的反应
  • 批准号:
    9911856
  • 财政年份:
    2020
  • 资助金额:
    $ 7.6万
  • 项目类别:
Inhibition of Candida virulence and biofilm formation by a bacterial peptide
细菌肽抑制念珠菌毒力和生物膜形成
  • 批准号:
    10407531
  • 财政年份:
    2018
  • 资助金额:
    $ 7.6万
  • 项目类别:
Post-initiation regulatory mechanisms controlling ethanolamine utilization
控制乙醇胺利用的引发后调节机制
  • 批准号:
    9193056
  • 财政年份:
    2015
  • 资助金额:
    $ 7.6万
  • 项目类别:
Mechanism of Gene Regulation by RNA-Binding ANTAR Proteins
RNA结合ANTAR蛋白的基因调控机制
  • 批准号:
    8325259
  • 财政年份:
    2011
  • 资助金额:
    $ 7.6万
  • 项目类别:

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A novel motility system driven by two classes of bacterial actins MreB
由两类细菌肌动蛋白 MreB 驱动的新型运动系统
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细菌肌动蛋白分离质粒的结构基础
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    278338
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    2013
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    $ 7.6万
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Cytoplasmic Actins in Maintenance of Muscle Mitochondria
细胞质肌动蛋白在维持肌肉线粒体中的作用
  • 批准号:
    8505938
  • 财政年份:
    2012
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    $ 7.6万
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Differential Expression of the Diverse Plant Actins
多种植物肌动蛋白的差异表达
  • 批准号:
    7931495
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    2009
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Studies on how actins and microtubules are coordinated and its relevancy.
研究肌动蛋白和微管如何协调及其相关性。
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  • 财政年份:
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Suppression of Arabidopsis Reproductive Actins
拟南芥生殖肌动蛋白的抑制
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    6655612
  • 财政年份:
    2003
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Suppression of Arabidopsis Reproductive Actins
拟南芥生殖肌动蛋白的抑制
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肌球蛋白与单体肌动蛋白的相互作用
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肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
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  • 财政年份:
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