Molecular Basis of Human Toxoplasmosis

人类弓形虫病的分子基础

基本信息

  • 批准号:
    8920930
  • 负责人:
  • 金额:
    $ 53.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-02-15 至 2020-01-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Toxoplasma gondii is a common parasitic infection of humans where it normally causes uncomplicated yet persistent infections. Reactivation of chronic infection can lead to severe disease in immunocompromised patients, including those with HIV-AIDS. With the advent of HAART therapy, the frequency of toxoplasmosis has decreased. However, there are still many areas of the world, and susceptible patient populations, were advanced HAART therapy is not widely or effectively implemented. Hence, toxoplasmosis presents a continued risk to immunocompromised patients due to the high prevalence of chronic infection and limitations of existing antibiotics, which do not eradicate chronic infections. Our studies are designed to define the molecular basis of pathogenesis in T. gondii, focusing on more virulent parasite lineages that may pose greater risk in immunocompromised patients. We have previously used genetic analyses of the clonal lineages of North America to identify virulence genes in T. gondii. However, T. gondii strains are much more diverse and undergo greater genetic exchange in other regions of the world. For example, the majority of South American strains are acutely virulent in the mouse model and such strains are frequently found in HIV positive patients where they cause severe CNS disease. The basis for this enhanced pathogenicity is presently unknown, but importantly, it cannot be explained by known virulence determinants. In preliminary studies, we have developed several new genetic crosses between highly virulent South American strains and less virulent lineages typical of North America. The proposed studies will use genetic mapping to identify virulence determinants of T. gondii and test the role of these parasite effectors in mediating survival in human cells. In preliminary studies, we have shown that IFN--activated human cells restrict the growth of T. gondii in a strain-specific manner. The proposed studies will define the cellular and molecular basis of this resistance pathway in human cells. Genetic approaches will be used to identify the molecular determinants of parasite virulence. The overall goal of our studies is to define the molecular mechanisms by which T. gondii overcomes host resistance, thus enhancing its survival and leading to more severe disease. Successful identification of parasite virulence factors may lead to improved detection and/or improved interventions designed to combat infection.
 描述(由申请人提供):弓形虫是一种常见的人类寄生虫感染,通常会引起简单但持续的感染。慢性感染的重新激活可导致免疫功能低下患者(包括艾滋病毒/艾滋病患者)的严重疾病。随着HAART疗法的出现,弓形虫病的发生率有所下降。然而,世界上仍有许多地区和易感患者群体没有广泛或有效地实施先进的HAART治疗。因此,由于慢性感染的高患病率和现有抗生素的局限性,弓形虫病对免疫功能低下的患者构成持续的风险,这些抗生素不能根除慢性感染。我们的研究旨在确定T.弓形虫,重点是更致命的寄生虫谱系,可能会造成更大的风险,在免疫功能低下的病人。我们以前曾使用北美克隆谱系的遗传分析,以确定毒力基因在T。刚地。然而,T.在世界其他地区,弓形虫菌株的多样性要大得多,基因交流也更频繁。例如,大多数南美菌株在小鼠模型中是急性毒性的,并且这些菌株经常在HIV阳性患者中发现,在那里它们引起严重的CNS疾病。这种增强的致病性的基础目前尚不清楚,但重要的是,它不能用已知的毒力决定因素来解释。在初步研究中,我们已经开发了几种新的南美洲高毒力菌株和北美典型的低毒力谱系之间的遗传杂交。拟开展的研究将利用遗传作图来鉴定T.并测试这些寄生虫效应器在介导人类细胞存活中的作用。在初步的研究中,我们已经表明IFN-γ激活的人类细胞限制T细胞的生长。以一种特定的方式。拟议的研究将确定人类细胞中这种耐药途径的细胞和分子基础。遗传学方法将用于确定寄生虫毒力的分子决定因素。我们研究的总体目标是 定义T.弓形虫克服了宿主的抵抗力,从而提高了其存活率,并导致更严重的疾病。寄生虫毒力因子的成功鉴定可能导致改进的检测和/或改进的旨在对抗感染的干预措施。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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L. David Sibley其他文献

ワークショップ 本邦におけるトキソプラズマ分離株の分子タイピング
日本弓形虫分离株的分子分型研讨会
  • DOI:
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    0
  • 作者:
    永宗喜三郎;喜屋武向子;山本徳栄;山野安規徳;Asis Khan;L. David Sibley
  • 通讯作者:
    L. David Sibley
Protozoan persister-like cells and drug treatment failure
原生动物类持久性细胞与药物治疗失败
  • DOI:
    10.1038/s41579-019-0238-x
  • 发表时间:
    2019-08-23
  • 期刊:
  • 影响因子:
    103.300
  • 作者:
    Michael P. Barrett;Dennis E. Kyle;L. David Sibley;Joshua B. Radke;Rick L. Tarleton
  • 通讯作者:
    Rick L. Tarleton
A combination of four emToxoplasma gondii/em nuclear-targeted effectors protects against interferon gamma-driven human host cell death
四种针对弓形虫核的效应蛋白的组合可防止干扰素γ驱动的人类宿主细胞死亡
  • DOI:
    10.1128/mbio.02124-24
  • 发表时间:
    2024-08-30
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Brittany Henry;Aubrey J. Phillips;L. David Sibley;Alex Rosenberg
  • 通讯作者:
    Alex Rosenberg
Cerebral Malaria Is Regulated by Host-Mediated Changes in emPlasmodium/em Gene Expression
脑型疟疾受宿主介导的疟原虫基因表达变化调节
  • DOI:
    10.1128/mbio.03391-22
  • 发表时间:
    2023-04-10
  • 期刊:
  • 影响因子:
    4.700
  • 作者:
    Clare K. Cimperman;Mirna Pena;Sohret M. Gokcek;Brandon P. Theall;Meha V. Patel;Anisha Sharma;ChenFeng Qi;Daniel Sturdevant;Louis H. Miller;Patrick L. Collins;Susan K. Pierce;Munir Akkaya;L. David Sibley
  • 通讯作者:
    L. David Sibley
No more free lunch
天下没有免费的午餐
  • DOI:
    10.1038/415843a
  • 发表时间:
    2002-02-21
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    L. David Sibley
  • 通讯作者:
    L. David Sibley

L. David Sibley的其他文献

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{{ truncateString('L. David Sibley', 18)}}的其他基金

Cryptosporidiosis and Oral Tolerance
隐孢子虫病和口服耐受
  • 批准号:
    10741600
  • 财政年份:
    2023
  • 资助金额:
    $ 53.75万
  • 项目类别:
Regulation of host cell egress by Toxoplasma gondii
弓形虫对宿主细胞出口的调节
  • 批准号:
    10640220
  • 财政年份:
    2022
  • 资助金额:
    $ 53.75万
  • 项目类别:
Regulation of host cell egress by Toxoplasma gondii
弓形虫对宿主细胞出口的调节
  • 批准号:
    10441782
  • 财政年份:
    2022
  • 资助金额:
    $ 53.75万
  • 项目类别:
Reactivation of Chronic Toxoplasmosis
慢性弓形虫病的重新激活
  • 批准号:
    10239417
  • 财政年份:
    2021
  • 资助金额:
    $ 53.75万
  • 项目类别:
Interferon-mediated control mechanisms in human cells
人类细胞中干扰素介导的控制机制
  • 批准号:
    10041166
  • 财政年份:
    2020
  • 资助金额:
    $ 53.75万
  • 项目类别:
Interferon-mediated control mechanisms in human cells
人类细胞中干扰素介导的控制机制
  • 批准号:
    10194376
  • 财政年份:
    2020
  • 资助金额:
    $ 53.75万
  • 项目类别:
Effect of Microbial Metabolites on Growth of Cryptosporidium
微生物代谢产物对隐孢子虫生长的影响
  • 批准号:
    9927337
  • 财政年份:
    2019
  • 资助金额:
    $ 53.75万
  • 项目类别:
Effect of Microbial Metabolites on Growth of Cryptosporidium
微生物代谢产物对隐孢子虫生长的影响
  • 批准号:
    10303025
  • 财政年份:
    2019
  • 资助金额:
    $ 53.75万
  • 项目类别:
Effect of Microbial Metabolites on Growth of Cryptosporidium
微生物代谢产物对隐孢子虫生长的影响
  • 批准号:
    10527363
  • 财政年份:
    2019
  • 资助金额:
    $ 53.75万
  • 项目类别:
INHIBITION OF STAT TRANSCRIPTION BY TOXOPLASMA
弓形虫对 STAT 转录的抑制
  • 批准号:
    9244190
  • 财政年份:
    2016
  • 资助金额:
    $ 53.75万
  • 项目类别:

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