Role of c-Myc up-regulation in Toxoplasma infection

 描述(由申请人提供)： 弓形虫是一种普遍存在的病原体，几乎在温血动物的任何有核细胞中感染和繁殖。这种单细胞真核细胞具有重要的医学意义，尤其是因为艾滋病患者的感染可能导致危及生命的疾病。虽然抗逆转录病毒疗法(ART)的使用降低了有机会获得治疗的西方国家弓形体脑炎(TE)的发病率，但在艾滋病毒诊断较晚或无法获得ART的人中，它仍然是一种与艾滋病相关的重大机会性感染。我们的结果表明，在弓形虫感染的人细胞中，诱导了一个关键的宿主调节因子c-Myc。重要的是，c-Myc的增加不是非特异性宿主免疫反应的结果，因为密切相关的细胞内寄生虫犬新孢子虫不会引起这种表型。此外，同时感染弓形虫和新孢子虫的细胞导致宿主c-Myc的增加，表明c-Myc被弓形虫主动上调(而不是被新孢子菌抑制)。在这里，我们提出了一种新的方法，利用本实验室和其他实验室开发的弓形虫基因工具，结合c-Myc领域开发的尖端技术来研究c-Myc在弓形虫感染过程中的调控机制和作用。本研究将验证一种假设，即弓形虫感染宿主细胞中c-Myc的激活是由弓形虫特异性基因(S)介导的。正向遗传筛选已经产生了这种效应的候选基因，该基因的突变将被用来揭示c-Myc诱导的机制以及c-Myc诱导在弓形虫感染中的作用。这项研究的结果将揭示弓形虫与宿主相互作用的有价值的信息 并可能在未来的研究中干扰c-Myc的诱导，作为一种治疗感染的新方法。

 DESCRIPTION (provided by applicant): Toxoplasma is a ubiquitous pathogen that infects and reproduces in virtually any nucleated cell of warm- blooded animals. This single-celled eukaryote is of great medical importance not least because infections in AIDS patients can lead to life-threatening illness. While use of anti-retroviral treatments (ART) has reduced the incidence of Toxoplasmic encephalitis (TE) in western countries with access to the therapy, it remains a significant AIDS-related opportunistic infection among people with late HIV diagnosis or without access to ART. Our results show that a key host regulator, c-Myc, is induced in human cells infected by Toxoplasma. Importantly, the increase of c-Myc is not a result of a nonspecific host immune response, as the closely related intracellular parasite, Neospora caninum, does not elicit this phenotype. Furthermore, a coinfection of cells with both Toxoplasma and Neospora results in an increase in host c-Myc showing that c-Myc is actively upregulated by Toxoplasma (rather than repressed by Neospora). Here, we propose a novel approach that employs genetic tools for Toxoplasma, developed in this and other labs, with cutting-edge technologies developed in the c-Myc field to examine the mechanism and role of c-Myc regulation during Toxoplasma infection. This study will test the hypothesis that the activation of c-Myc in Toxoplasma-infected host cells is mediated by specific Toxoplasma gene(s). Forward genetic screens have already yielded a candidate gene for this effect and mutants in this gene will be used to uncover the mechanism underlying c-Myc induction as well as the role of c-Myc induction in the context of Toxoplasma infection. The results of this study will reveal valuable information about Toxoplasma's interaction with its host and make possible future investigation aimed at interfering with c-Myc induction as a novel treatment for the infection.