INHIBITION OF STAT TRANSCRIPTION BY TOXOPLASMA

弓形虫对 STAT 转录的抑制

基本信息

  • 批准号:
    9244190
  • 负责人:
  • 金额:
    $ 22.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-12-05 至 2018-11-30
  • 项目状态:
    已结题

项目摘要

Toxoplasma gondii is a widespread parasite of animals that causes zoonotic infection in humans. Although acute infections in healthy adults are normally resolved without serious consequences, infection of immunocompromised individuals can lead to serious complications. Additionally, because chronic infections are not cleared by the immune system or by normal antibiotic treatment, individuals remain chronically infected for life. The presence of semi-dormant tissue cysts that can reactivate predisposes infected individuals to the risk of complications in the event of waning immunity. One of the key features of T. gondii that enables it to persist in the host is the ability to block immune responses, and thereby prevent clearance of the parasite. Among the pathways that are perturbed by T. gondii infection are the signal transducer and activator of transcription (STAT) family of transcription factors. Control of T. gondii infection relies on activation of STAT1 by IFN-γ, which is essential to upregulate antimicrobial pathways in both hematopoietic and non-hematopoietic cells. However, when cells are infected by T. gondii before encountering IFN-γ, the parasite is able to block STAT1-mediated transcription resulting in reduced control of infection. Global analysis of gene expression reveals that the majority of IFN-γ-activated genes are blocked by prior infection with T. gondii. The block in STAT1 signaling occurs in both rodent and human cells, although the molecular basis for this trait has not been previously identified. In preliminary studies we have identified a T. gondii protein that binds to phosphorylated STAT1 dimers and prevents activation of downstream genes. This effector, known as T. gondii Inhibitor of STAT Transcription (TgIST) blocks IFN-γ-induced gene expression mediated by STAT1. TgIST is both necessary and sufficient for blocking STAT1- mediated transcription in mouse and human cells. TgIST binds to a host repressor complex that alters chromatin structure. The proposed studies will define the role of host chromatin modifiers in modulating STAT1 transcriptional complexes using gene disruption by CRISPR/Cas9 combined with various reporter assays. Additionally, we will implement a variety of cellular, biochemical, and genetic methods to define the domains necessary for export and trafficking of TgIST to the host cell nucleus, where it is active.
刚地弓形虫是一种广泛存在于动物体内的寄生虫,可引起人畜共患病

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:
    $ 22.88万
  • 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:
    $ 22.88万
  • 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:
    $ 22.88万
  • 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:
    $ 22.88万
  • 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:
    $ 22.88万
  • 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:
    $ 22.88万
  • 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:
    $ 22.88万
  • 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:
    $ 22.88万
  • 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:
    $ 22.88万
  • 项目类别:
Molecular Basis of Human Toxoplasmosis
人类弓形虫病的分子基础
  • 批准号:
    10557864
  • 财政年份:
    2015
  • 资助金额:
    $ 22.88万
  • 项目类别:

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