This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The protozoan parasite Toxoplasma gondii is an important human and veterinary pathogen. Because of the late development of the cellular immune response during fetal maturation, T. gondii is a leading cause of congenital neurological birth defects. In recent years, Toxoplasma has also achieved notoriety as a cause of life-threatening opportunistic disease in immunocompromised individuals.Asexual replication of T. gondii is characterized by two forms: rapidly growing 'tachyzoites' that are sensitive to the immune system and several drugs, and the slowly dividing encysted 'bradyzoites' that evade both the host's immune response and current drug treatment. Bradyzoites remain latent within most tissues for many years, representing a threat to immunocompromised patients. There is no effective treatment for chronic toxoplasmosis due to a lack of drugs capable of eliminating tissue cysts. Therefore, the differentiation process represents an important target for both vaccine and drug development.Tachyzoites are readily cultured in the laboratory, and recent work by many groups has provided methods for studying bradyzoite differentiation in vitro. To date, genetic knock-outs carried out on bradyzoite specific genes have failed to identify a single gene that is essential for bradyzoite formation or survival. In an effort to identify genes that are essential for cyst formation we have developed a selection scheme for parasites that are unable to differentiate and we have isolated bradyzoite differentiation mutants (Matrajt et al, 2002). Our lab is now scaling-up the same screen as well as exploring similar strategies to isolate additional mutants, define genetic pathways that regulate bradyzoite differentiation, and identify genes that play a central role in T. gondii development. One of the bradyzoite differentiation mutants identified in this screen (mutant B7) was found to be defective in many aspects of differentiation. The disrupted locus, named B41, has been identified and the expression of a developmentally regulated transcript has been abolished in the mutant parasites.
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