NOVEL CELLULAR & GENETIC ANALYSES USING A NEW CHLAMYDIA PENETRANT PEPTIDE

新颖的蜂窝

基本信息

  • 批准号:
    8281426
  • 负责人:
  • 金额:
    $ 17.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-06-15 至 2014-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The objectives of this proposal are to elucidate the mechanism by which Chlamydia trachomatis evades the immune response by attenuating IFN?-dependent signaling in infected host cells, and to develop a new reverse genetic strategy to study C. trachomatis pathogenesis and biology. Sexually transmitted C. trachomatis infections, primarily caused by serovars D-F, are a major public health concern with adverse effects on female fertility and neonatal health. Despite significant public health interventions including education, screening and treatment, reported cases n the US reached 1 million in 2006 and continue to rise, resulting in annual health care costs >$2.4 billion. Asymptomatic infections in >70% of women and >30% of men, can take months to years to resolve, and thereby compounding transmission of C. trachomatis. Transmission is exacerbated by short-lived protection to re-infection. In vitro studies in human epithelial cells, and animal studies using C. muridarum, have demarcated IFN? as a major anti-chlamydial mediator. In vivo, although elevated IFN??is found in the infected human endocervix, clinical data indicate that C. trachomatis can evade immune responses. We have developed an innovative approach using a novel penetrant peptide (CPP) to label C. trachomatis Elementary Bodies (EB). Our approach has permitted the isolation of pure populations of infected endocervical epithelial cells, from mixed pools of cells exposed to C. trachomatis. Analyses of pure populations has revealed that C. trachomatis attenuates IFN?-dependent expression of indoleamine-2,3-dioxygenase (IDO1). Attenuation permits C. trachomatis, a tryptophan auxotroph, to ameliorate the effect of intracellular tryptophan depletion by IDO1. The first goal of this application is to understand how Chlamydia blocks host-cell IFN?-dependent signaling. Understanding this mechanism will permit development of new strategies that target immune evasion by C. trachomatis. The paucity of easily applicable genetic tools to manipulate C. trachomatis has limited the capacity to investigate mechanisms employed by C. trachomatis that drive immune evasion and pathogenesis. This application addresses this significant deficiency by proposing an innovative approach using the same CPP to carry cargoes that repress expression of specific C. trachomatis genes. When developed and validated, our strategy will permit robust reverse genetic approaches to molecularly dissect virulence determinants of C. trachomatis. These studies with our novel CPP will significantly shift current paradigms and revolutionize approaches in Chlamydia research by: 1) Establishing a robust method to elucidate previously unidentified immune evasion strategies used by C. trachomatis; and 2) Providing, for the first time, a robust reverse genetic technique to dissect the role of specific bacterial genes in the developmental cycle and pathogenesis.
描述(申请人提供):这项建议的目的是阐明沙眼衣原体通过减弱感染宿主细胞中依赖干扰素的信号来逃避免疫反应的机制,并开发一种新的反向遗传策略来研究沙眼衣原体的发病机制和生物学。 性传播沙眼衣原体感染,主要由D-F血清型引起,是一个主要的公共卫生问题,对女性生育和新生儿健康产生不利影响。尽管采取了包括教育、筛查和治疗在内的重大公共卫生干预措施,但美国报告的病例在2006年达到100万例,而且还在继续上升,导致每年的医疗保健费用>24亿美元。在70%的女性和30%的男性中,无症状感染可能需要几个月到几年的时间才能解决,从而加剧了沙眼衣原体的传播。对再次感染的短暂保护加剧了传播。对人类上皮细胞的体外研究和对小鼠隐孢子虫的动物研究已经确定了干扰素?作为主要的抗衣原体调停剂。在体内,虽然在感染的人子宫内膜中发现了高水平的干扰素α,但临床数据表明沙眼衣原体可以逃避免疫反应。 我们开发了一种创新的方法,使用一种新的穿透性多肽(CPP)来标记沙眼衣原体基本体(EB)。我们的方法允许从暴露于沙眼衣原体的混合细胞池中分离出受感染的宫颈上皮细胞的纯群体。对纯种群的分析表明,沙眼衣原体可减弱依赖干扰素的吲哚胺-2,3-双加氧酶(IDO1)的表达。衰减允许沙眼衣原体,一种色氨酸营养缺陷型,改善IDO1对细胞内色氨酸耗竭的影响。这个应用程序的第一个目标是了解衣原体如何阻止宿主细胞依赖干扰素?的信号。了解这一机制将有助于开发针对沙眼衣原体免疫逃避的新策略。 缺乏易于应用的基因工具来操纵沙眼衣原体,限制了研究沙眼衣原体驱动免疫逃避和致病机制的能力。这项申请通过提出一种创新的方法来解决这一重大缺陷,该方法使用相同的CPP来运输抑制特定沙眼衣原体基因表达的货物。当开发和验证时,我们的策略将允许强大的反向遗传方法来分子剖析沙眼衣原体的毒力决定因素。 我们的这些新型CPP研究将显著改变目前的研究范式,并通过以下方式彻底改变衣原体研究的方法:1)建立一种强大的方法来阐明沙眼衣原体以前未知的免疫逃避策略;以及2)首次提供一种强大的反向遗传技术来剖析特定细菌基因在发育周期和发病机制中的作用。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The High-Risk Human Papillomavirus E6 Oncogene Exacerbates the Negative Effect of Tryptophan Starvation on the Development of Chlamydia trachomatis.
高风险人乳头瘤病毒 E6 癌基因加剧了色氨酸饥饿对沙眼衣原体发育的负面影响。
  • DOI:
    10.1371/journal.pone.0163174
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Sherchand,ShardulendraP;Ibana,JoyceA;Zea,ArnoldH;Quayle,AlisonJ;Aiyar,Ashok
  • 通讯作者:
    Aiyar,Ashok
Chlamydia trachomatis-infected cells and uninfected-bystander cells exhibit diametrically opposed responses to interferon gamma.
  • DOI:
    10.1038/s41598-018-26765-y
  • 发表时间:
    2018-05-31
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Ibana JA;Sherchand SP;Fontanilla FL;Nagamatsu T;Schust DJ;Quayle AJ;Aiyar A
  • 通讯作者:
    Aiyar A
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Ashok A Aiyar其他文献

Ashok A Aiyar的其他文献

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{{ truncateString('Ashok A Aiyar', 18)}}的其他基金

Factors that modulate the deleterious effect of ammonia generation by chlamydial tryptophan synthase
调节衣原体色氨酸合酶产生氨有害作用的因素
  • 批准号:
    10198719
  • 财政年份:
    2020
  • 资助金额:
    $ 17.75万
  • 项目类别:
Factors that modulate the deleterious effect of ammonia generation by chlamydial tryptophan synthase
调节衣原体色氨酸合酶产生氨有害作用的因素
  • 批准号:
    10040215
  • 财政年份:
    2020
  • 资助金额:
    $ 17.75万
  • 项目类别:
Consequences of vaginal microbiota on IFNγ-mediated clearance of Chlamydia trachomatis
阴道微生物群对 IFNγ 介导的沙眼衣原体清除的影响
  • 批准号:
    9240286
  • 财政年份:
    2017
  • 资助金额:
    $ 17.75万
  • 项目类别:
Consequences of vaginal microbiota on IFNγ-mediated clearance of Chlamydia trachomatis
阴道微生物群对 IFNγ 介导的沙眼衣原体清除的影响
  • 批准号:
    9540785
  • 财政年份:
    2017
  • 资助金额:
    $ 17.75万
  • 项目类别:
NOVEL CELLULAR & GENETIC ANALYSES USING A NEW CHLAMYDIA PENETRANT PEPTIDE
新颖的蜂窝
  • 批准号:
    8166018
  • 财政年份:
    2011
  • 资助金额:
    $ 17.75万
  • 项目类别:
Characterization and use of a novel AT-hook protein in Leishmania
利什曼原虫新型 AT-hook 蛋白的表征和应用
  • 批准号:
    8071117
  • 财政年份:
    2010
  • 资助金额:
    $ 17.75万
  • 项目类别:
Characterization and use of a novel AT-hook protein in Leishmania
利什曼原虫新型 AT-hook 蛋白的表征和应用
  • 批准号:
    7896108
  • 财政年份:
    2010
  • 资助金额:
    $ 17.75万
  • 项目类别:
Functions of EBNA1 in replication & partitioning of EBV
EBNA1 在复制中的功能
  • 批准号:
    7116680
  • 财政年份:
    2005
  • 资助金额:
    $ 17.75万
  • 项目类别:
Functions of EBNA1 in replication & partitioning of EBV
EBNA1 在复制中的功能
  • 批准号:
    6937180
  • 财政年份:
    2005
  • 资助金额:
    $ 17.75万
  • 项目类别:
Functions of EBNA1 in replication & partitioning of EBV
EBNA1 在复制中的功能
  • 批准号:
    7846932
  • 财政年份:
    2005
  • 资助金额:
    $ 17.75万
  • 项目类别:

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