Role of amylopectin granules in chronic toxoplasmosis, an HIV-AIDS defining infection

支链淀粉颗粒在慢性弓形体病(一种 HIV-AIDS 感染)中的作用

基本信息

  • 批准号:
    10025481
  • 负责人:
  • 金额:
    $ 19.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-03-05 至 2022-02-28
  • 项目状态:
    已结题

项目摘要

Project Summary A distinguishing characteristic of tissue cyst forming Apicomplexa, like Toxoplasma gondii, is the accumulation of amylopectin (starch) granules (AG) within bradyzoites and their absence within the actively growing tachyzoite forms. As polymers of glucose, AG functions as a battery serving as a reserve for energy production and biosynthetic functions. Our recent work established that bradyzoites retain significant replicative potential within tissue cysts in vivo. Notably, most bradyzoite replication within tissue cysts occurs asynchronously with clustered bursts of growth interceded with non-replicative periods. While the specific signals triggering these bursts remain unknown, what is clear is that they would require substantial energy and metabolite inputs to execute. Historical evidence and our findings reveal that AG levels within encysted bradyzoites are highly variable with clusters of parasites lacking AGs adjacent to others that are loaded with starch. This suggests that AG metabolism involving both synthesis and turnover are active within tissue cysts and may play a central role in the progression of chronic toxoplasmosis. We will directly address the dynamics and biological contributions of AGs in the progression of the chronic infection at the level of individual bradyzoites using novel tools and concepts developed in our recently published work. The variable levels of AG, within encysted bradyzoites, suggest that both AG accumulation and depletion are under regulatory control. Indeed the enzymatic machinery required for both the synthesis and regulated turnover of starch are encoded in the Toxoplasma genome. We will directly test the importance of AG in the acute infection, the regulation of stage conversion and the establishment/ progression of the chronic infection by targeting the commitment enzyme for starch synthesis, the UDP-glucose pyrophosphorylase (TgUDP-GPP, TgME49_218200), and the starch synthase (TgSS, TgME49_222800). Recent evidence suggests that despite being morphologically (though not biochemically) detectable, amylopectin may play a role in tachyzoite intermediary metabolism as well. In addition, the contribution of AG's to reactivation, the primary trigger of symptomatic disease in HIV-AIDS will be addressed in the context of induced immune suppression. With the proposed studies we aim to dissect the previously unexplored role of AG in tachyzoites, as factors in tachyzoite to bradyzoite conversion, the progression of the chronic infection and clinically critical reactivation in vivo. These studies will establish the groundwork for targeting AG metabolism for therapeutic intervention in the chronic infection where the paucity of effective drugs remains a significant issue in the clinical context of HIV-AIDS.
项目总结

项目成果

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专利数量(0)

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ANTHONY P. SINAI其他文献

ANTHONY P. SINAI的其他文献

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{{ truncateString('ANTHONY P. SINAI', 18)}}的其他基金

Extragenic adaptation to the loss of a deubiquitinase affecting the T. gondii cell cycle and development
对影响弓形虫细胞周期和发育的去泛素酶损失的外源适应
  • 批准号:
    9914617
  • 财政年份:
    2020
  • 资助金额:
    $ 19.13万
  • 项目类别:
The cell cycle of T. gondii bradyzoites within tissue cysts:in vivo development of an HIV-AIDS opportunistic parasite
组织包囊内弓形虫缓殖子的细胞周期:HIV-AIDS机会性寄生虫的体内发育
  • 批准号:
    9207417
  • 财政年份:
    2016
  • 资助金额:
    $ 19.13万
  • 项目类别:
Host glycosyltransferases in the glycosylation of Toxoplasma proteins
弓形虫蛋白糖基化中的宿主糖基转移酶
  • 批准号:
    8605834
  • 财政年份:
    2013
  • 资助金额:
    $ 19.13万
  • 项目类别:
Host glycosyltransferases in the glycosylation of Toxoplasma proteins
弓形虫蛋白糖基化中的宿主糖基转移酶
  • 批准号:
    8451142
  • 财政年份:
    2013
  • 资助金额:
    $ 19.13万
  • 项目类别:
Contribution of N-glycosylation to the Toxoplasma glycoproteome
N-糖基化对弓形虫糖蛋白质组的贡献
  • 批准号:
    8432797
  • 财政年份:
    2012
  • 资助金额:
    $ 19.13万
  • 项目类别:
Contribution of N-glycosylation to the Toxoplasma glycoproteome
N-糖基化对弓形虫糖蛋白质组的贡献
  • 批准号:
    8320531
  • 财政年份:
    2012
  • 资助金额:
    $ 19.13万
  • 项目类别:
Novel activities and the T. gondii vacuolar membrane
新活性和弓形虫液泡膜
  • 批准号:
    8197685
  • 财政年份:
    2010
  • 资助金额:
    $ 19.13万
  • 项目类别:
Novel activities and the T. gondii vacuolar membrane
新活性和弓形虫液泡膜
  • 批准号:
    8029051
  • 财政年份:
    2010
  • 资助金额:
    $ 19.13万
  • 项目类别:
Proteomic analysis of the T. gondii vacuolar membrane
弓形虫液泡膜的蛋白质组学分析
  • 批准号:
    6968901
  • 财政年份:
    2005
  • 资助金额:
    $ 19.13万
  • 项目类别:
Proteomic analysis of the T. gondii vacuolar membrane
弓形虫液泡膜的蛋白质组学分析
  • 批准号:
    7140472
  • 财政年份:
    2005
  • 资助金额:
    $ 19.13万
  • 项目类别:

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