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Host factor regulation of Toxoplasma gondii growth and differentiation.

机译:弓形虫生长和分化的宿主因子调节。

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摘要

Toxoplasma gondii is an obligate intracellular protozoan parasite that infects a wide range of mammalian and avian hosts, including up to one third of the human population. Immunocompetent individuals clear acute infection with the parasite, however chronic infection is always established and persists for the life of the infected host. Reactivation of chronic infection in immunocompromised individuals, and vertical transmission from mother to fetus during acute infection can cause devastating neural pathology. Acute and chronic infection are associated with two distinct forms of the parasite: tachyzoites, which are fast replicating and responsible for acute infection and bradyzoites, which are slow replicating and establish chronic tissue cysts. During the course of infection, tachyzoites differentiate into bradyzoites. While tachyzoites can infect and replicate within virtually any nucleated cell, bradyzoite cysts typically only develop within neural and muscle tissue. Despite the critical importance of bradyzoite development to T. gondii pathogenesis, the factors responsible for this tissue tropism are unclear. Specifically, there are few defined molecular characteristics of the host cell that have been shown to regulate parasite growth and differentiation as bradyzoites.Using an optimized in vitro system of bradyzoite induction, we have identified several new mechanisms by which T. gondii stage conversion is regulated in vitro. First, we have shown that enhancement of host cell glycolysis can support continued tachyzoite growth under metabolic stress conditions and thus inhibit bradyzoite conversion in a cell-intrinsic manner. Second, we have shown that cell lines that are intrinsically resistant to conversion, either basally or due to the induction of glycolysis, surprisingly release soluble mediators that inhibit conversion in trans. Finally, we have defined a new metabolic function for host Akt in T. gondii differentiation. These results suggest two new hypotheses as to how growth and differentiation of T. gondii may be regulated in vivo. One, the preferential encystment seen in highly glycolytic tissues may be a result of the ability of these tissues to sustain enhanced tachyzoite growth and increased parasite load, and if conversion from tachyzoites to bradyzoites is spontaneously occurring at some level in vivo, increased parasite load may lead to a higher incidence of cyst development in these tissues. Two, cells may broadly be releasing inhibitory mediators, making many tissues inhospitable to conversion, and thus restricting cyst development to particular tissues. While the in vivo significance of these hypotheses remains to be investigated, they provide a new metabolic framework within which the mechanisms that regulate tachyzoite to bradyzoite conversion in vivo can be investigated.
机译:弓形虫是专性的细胞内原生动物寄生虫,可感染多种哺乳动物和鸟类宿主,包括多达三分之一的人口。免疫能力强的个体清除了寄生虫的急性感染,但是慢性感染始终存在,并且在感染宿主的生命中持续存在。免疫功能低下的个体中慢性感染的重新激活以及急性感染期间从母亲到胎儿的垂直传播会导致破坏性的神经病理。急性和慢性感染与两种不同形式的寄生虫有关:速殖子和速殖子,速殖子快速复制并负责急性感染,缓殖子慢速复制并形成慢性组织囊肿。在感染过程中,速殖子分化为缓殖子。速殖子几乎可以在任何有核细胞内感染和复制,而缓殖子囊肿通常仅在神经和肌肉组织内形成。尽管缓殖子发育对弓形虫发病机理至关重要,但尚不清楚造成这种组织嗜性的因素。具体来说,很少有宿主细胞定义的分子特征被证明能以缓殖子的形式调节寄生虫的生长和分化。通过优化的缓殖子体外诱导系统,我们发现了调节刚地弓形虫阶段转化的几种新机制。体外。首先,我们已经表明增强宿主细胞糖酵解可以支持在代谢应激条件下速殖子的持续生长,从而以细胞内在的方式抑制缓殖子的转化。第二,我们已经表明,无论是基础上还是由于糖酵解的诱导,内在地对转化具有抗性的细胞系出人意料地释放出可溶的介体,从而抑制了反式转化。最后,我们定义了弓形虫分化中宿主Akt的新代谢功能。这些结果提出了关于如何在体内调节弓形虫的生长和分化的两个新假设。第一,在高度糖酵解组织中看到的优先包囊可能是由于这些组织维持速殖子生长增强和寄生虫负荷增加的能力的结果,并且如果体内某些水平自发地将速殖子转化为缓殖子,则寄生虫负荷可能增加导致这些组织中发生囊肿的可能性更高。第二,细胞可能广泛地释放抑制性介质,使许多组织不宜进行转化,从而将囊肿发育限制在特定组织上。这些假说的体内意义尚待研究,但它们提供了新的代谢框架,可在其中研究调节速殖子向缓殖子转化的机制。

著录项

  • 作者

    Weilhammer, Dina Rae.;

  • 作者单位

    University of California, Berkeley.;

  • 授予单位 University of California, Berkeley.;
  • 学科 Biology Molecular.Biology Parasitology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 66 p.
  • 总页数 66
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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