: 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.
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