Blockade of host apoptosis by Toxoplasma gondii

描述(申请人提供)：弓形虫在细胞内生长 一种独特的寄生虫修饰的隔室，寄生虫性液泡(PV)。这个 PV由寄生液泡膜与寄主细胞质分离。 (PVM)。PVM在形态上的一个独特特征是它的亲密 与宿主线粒体和内质网(ER)的相关性。 PVM与线粒体的结合是由Ruptry派生的， ROP2家族的PVM定位蛋白。的密切联系 线粒体和PVM在寄生虫生物学中具有重要作用。 最近的证据表明，弓形虫感染的细胞 抗凋亡的。线粒体在传递过程中起着核心作用。 以及细胞凋亡刺激的执行。这项提案的目的是确定 弓形虫阻断宿主细胞凋亡的分子基础。给定 线粒体在细胞凋亡中的重要性及PVM-线粒体的作用 我们将研究细胞凋亡阻断过程中的相关性。凋亡信号是 被称为半胱氨酸酶的半胱氨酸蛋白酶家族传递和执行。这个 弓形虫感染对caspase活性和活性的影响 使用生化方法进行检查。最后，天津市寄生虫调解人(S) 阻断宿主细胞凋亡将使用基因组、 生物化学和遗传方法。遗传方法采用了一种新的筛查方法 根据弓形虫的保护能力鉴定和分离弓形虫突变体 受感染的细胞不受凋亡刺激。确定其分子基础 弓形虫介导的细胞凋亡阻断将揭示对 这种令人着迷的寄生虫对宿主功能的操纵。

DESCRIPTION (provided by applicant): Toxoplasma gondii grows in the cell within a unique parasite-modified compartment, the parasitophorous vacuole (PV). The PV is separated from the host cytoplasm by the parasitophorous vacuole membrane (PVM). A morphologically distinctive feature of the PVM is its intimate association with host mitochondria and endoplasmic reticulum (ER). PVM-mitochondrial association is mediated by the rhoptry derived, PVM-localizing proteins of the ROP2 family. The intimate association of mitochondria and the PVM suggests an important function in parasite biology. Recent evidence indicates that T. gondli infected cells are profoundly resistant to apoptosis. Mitochondria play a central role in the transmission and execution of apoptotic stimuli. The aim of this proposal is to identify the molecular basis of the blockade of host apoptosis by T. gondii. Given the importance of mitochondria in apoptosis, the role of PVM-mitochondrial association in the block of apoptosis will be examined. Apoptotic signals are transmitted and executed by a family of cysteine proteases called caspases. The effect of T. gondii infection on caspase activation and activity will be examined using biochemical approaches. Finally, the parasite mediator(s) of the blockade of host apoptosis will be identified using a combination of genomic, biochemical and genetic approaches. The genetic approach employs a novel screen to identify and isolate T. gondii mutants based on their inability to protect the infected cell from apoptotic stimuli. Identifying the molecular basis of the T. gondii mediated blockade of apoptosis will reveal novel insights into the manipulation of host functions by this fascinating parasite.