Trypansoma cruzi-induced host cell signaling responses

描述（由申请方提供）：动质体原生动物寄生虫克氏锥虫引起人类恰加斯病，这是一种慢性和使人衰弱的疾病，影响拉丁美洲数百万人。自T. cruzi是专性细胞内寄生虫，阐明建立感染所需的宿主-病原体相互作用对于理解T. Cruzi发病机制我们的初步研究结果强调，寄生液泡作为一个过渡点，T。cruzi细胞内生命周期，将早期信号传导和调节空泡形成和成熟的细胞变化与寄生虫从空泡中出现时引起的基因表达的下游变化联系起来。我们将对T. cruzi液泡的形成、成熟和破坏在分子和细胞水平上进行。利用诱导IFNb基因表达作为T. cruzi，我们将定义触发这种反应所需的宿主细胞信号通路。最后，我们将采用DNA微阵列分析，以进一步表征宿主对T。cruzi的特定目标是确定哪些变化是作为对T. cruzi感染与大多数由T.克鲁兹感染的细胞很少有人知道的分子和细胞的事件需要塑造一个允许的宿主细胞环境，这种病原体的细胞内生长和生存。我们提出的多方面的方法来检查这些早期事件将提供分子细节，目前缺乏我们的理解T。克氏感染过程对这些基本过程的理解将指导我们有效预防和控制恰加斯病的努力。

DESCRIPTION (provided by the applicant): The kinetoplastid protozoan parasite Trypanosoma cruzi causes Chagas' disease in humans, a chronic and debilitating condition affecting several million individuals in Latin America. Since the vertebrate stages of T. cruzi are obligate intracellular parasites, elucidation of host-pathogen interactions required for establishment of infection is crucial to understanding mechanisms of T. cruzi pathogenesis. Our preliminary findings highlight the parasitophorous vacuole as a transitional point the T. cruzi intracellular life cycle, linking early signaling and cellular changes regulating formation and maturation of the vacuole to downstream changes in gene expression evoked upon emergence of parasites from the vacuole. We will carry out a detailed analysis of the process of T. cruzi vacuole formation, maturation and disruption the molecular and cellular levels. Using the induction of IFNb gene expression as a sensitive reporter for host cell transcriptional responses elicited by vacuole egress by T. cruzi, we will define the host cell signaling pathways required to trigger this response. Finally, we will employ DNA microarray analysis to further characterize host transcriptional responses to T. cruzi with the specific goal of determining which changes are elicited as a primary response to T. cruzi infection versus the majority of secondary, tertiary, responses elicited by soluble factors released from T. cruzi-infected cells. Little is known regarding the molecular and cellular events required to shape a permissive host cell environment for intracellular growth and survival of this pathogen. The multi-faceted approach we propose to examine these early events will provide molecular detail currently lacking in our understanding of the T. cruzi infective process. It is the understanding of these basic processes that will guide our efforts toward effective prevention and control of Chagas' disease.