Toxoplasma Gondii Regulation of Host Gene Expression

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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.