Toxoplasma Gondii Regulation of Host Gene Expression

描述(申请人提供)：弓形虫是一种细胞内的 顶端复合体寄生虫，几乎可以感染任何有核脊椎动物细胞。 弓形虫病是由弓形虫引起的疾病，会导致严重甚至 免疫功能受损的个体和发育中的胎儿中的致命疾病。 感染最常见的原因是消化了受污染的肉类 含有充满寄生虫的组织包囊。一旦消化，囊肿就会破裂。 释放的寄生虫感染肠道。树突状细胞和 招募到弓形虫感染细胞的巨噬细胞被感染 并被寄生虫用来在宿主中传播。 参与这一过程的寄生虫分子和宿主细胞机制是 未知，但很可能是寄主病原体的重要组成部分 互动。作为F32资助的博士后研究员，布拉德博士检查了， 通过cDNA微阵列和完善的感染模型， 感染弓形虫的宿主细胞发生的转录变化。 在感染早期，在1-2小时内，许多 包括趋化因子和细胞因子在内的炎症反应转录本 调高了。与完整寄生虫类似，一种可溶性寄生虫衍生制剂 这些因素也上调了相同炎症因子的表达 回复记录。这种制剂是从细胞外产生的 寄生虫，以前被其他人证明是一种生理上的 弓形虫宿主免疫反应的相关激活物。因此，一个 已经开发出一种实验系统，可以用来识别寄生虫 向宿主细胞发出信号的分子。第一，寄主转录 弓形虫调控宿主的影响因素及信号转导途径 基因表达将被阐明。第二，释放出的可溶性因子 寄生虫将被提纯和克隆。最后，这些因素的重要性 调控基因表达的因子及其在寄生虫生长和发育中的作用 存活率将会被检查。这些数据将使我们更好地理解 弓形虫向宿主细胞发出信号的分子机制。 他们也为未来作为独立调查员的研究奠定了基础。 检查这些因子是如何从寄生虫中释放出来的，确定 相关的宿主细胞受体，并阐明这些分子在 致命性和疾病。

DESCRIPTION (provided by applicant): Toxoplasma gondii is an intracellular apicomplexan parasite that can infect almost any nucleated vertebrate cell. Toxoplasmosis, the disease caused by T. gondii, results in severe or even fatal disease in immunocompromised individuals and the developing fetus. Infection is most commonly caused by digestion of contaminated meat that contains tissue cysts filled with parasites. Once digested, the cysts rupture and the released parasites infect the intestine. Dendritic cells and macrophages recruited to the Toxoplasma-infected cells become infected themselves and are used by the parasite to disseminate throughout the host. The parasite molecules and host-cell machinery involved in this process are unknown but are likely to be important components of the host-pathogen interaction. As a F32 sponsored post-doctoral fellow, Dr. Blader examined, with cDNA microarrays and a well established infection model, the transcriptional changes that occur to host cells infected with Toxoplasma. Early during infection, within 1 - 2 hours, the expression of many inflammatory response transcripts including chemokines and cytokines were upregulated. Similar to intact parasites, a preparation of soluble parasitederive factors also up-regulated the expression of the same inflammatory response transcripts. This preparation is generated from extracellular parasites and was previously demonstrated by others to be a physiologically relevant activator of host immune responses to Toxoplasma. Thus, an experimental system has been developed that is poised to identify parasitederived molecules that signal to the host cell. First, the host transcription factors and signaling pathways that are involved in Toxoplasma-regulated host gene expression will be elucidated. Second, the soluble factors released from the parasite will be purified and cloned. Finally, the importance of these factors in modulating gene expression and their role in parasite growth and survival will be examined. These data will lead to a greater understanding of the molecular mechanisms that Toxoplasma employs to signal to its host cell. They also lay the foundation for future studies as an independent investigator examining how these factors are released from the parasite, identifying the relevant host cell receptors, and elucidating a role for these molecules in virulence and disease.