This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Toxoplasma gondii infects 1.5 million human subjects annually and ranks only behind the bacterial pathogens, Listeria and Salmonella, as a leading cause of infection-related death in the US [1,2]. Toxoplasma can be dangerous to the unborn, to patients undergoing chemotherapy or organ transplant, and to people with AIDS [2-5]. Bradyzoite development is ultimately responsible for permanent infection [6], and as such, morbidity and mortality is significant in the immunocompromised where bradyzoite-tachyzoite switching underlies the pathogenesis of clinical toxoplasmosis [5]. We have determined that selected trisubstituted pyrroles [11-13], will affect a human fibroblast to induce VEG-strain tachyzoites to undergo bradyzoite differentiation within 48 h post-infection. Our hypothesis is that these molecules induce bradyzoite development in VEG strain tachyzoites by modulating host cell gene expression, and that specific host cell pathways provide the primary signal that parasites monitor to time bradyzoite development. We have used DNA microarrays to identify 80 distinct mRNAs, whose expression is coincident with induced bradyzoite development. Early analyses of these mRNAs indicate that many can be directly or indirectly associated with growth regulatory pathways and the proliferative state of the host cell. We have concluded the trisubstituted pyrrole designated Compound 1 induces parasite tissue cyst development by modulating host cell transcription, and that new transcription events ultimately signal the parasite to establish a permanent infection. The ability to experimentally alter the host cell, such that, tachyzoites that invade are induced to initiate bradyzoite development provides new experimental strategies to study this phenomenon. Proteins encoded by these mRNAs help to define the molecular features of a specific host environment that is more (or less) conducive to bradyzoite differentiation, and may provide one or more targets for the treatment of this infection.
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