INTERCONNECTION BETWEEN ORGANELLAR FUNCTIONS, DEVELOPMENT AND DRUG-RESISTANCE IN THE PROTOZOAN PARASITE, TOXOPLASMA-GONDII

The protozoan parasite Toxoplasma gondii causes severe disease in anim als and humans, In AIDS patients, for example, the encephalitis it pro duces is a major cause of death, Part of the very successful strategy adopted by the parasite centers on its ability to differentiate from t he actively growing tachyzoite form to a chronic, almost latent state called the bradyzoite. The molecular signals and precise triggers invo lved in this differentiation process are not known. Drugs for treating toxoplasmosis are not capable of clearing the infection apparently be cause of their inability to eradicate the bradyzoites. Recently, as pa rt of our efforts to understand the mode of action of a promising new drug, atovaquone, we have generated and analysed a mutant that is resi stant to this drug, Surprisingly, we found that this mutant is predisp osed to spontaneously differentiate from the tachyzoite to bradyzoite form in vitro (Tomavo & Boothroyd, submitted), Given that atovaquone i s believed to act on the parasite mitochondria, we were interested to explore the relationship between mitochondrial function and differenti ation, We find that atovaquone and a number of other drugs targeted to mitochondria will cause wild type parasites to differentiate from tac hyzoites to bradyzoites suggesting some sort of adaptive response to a decrease in mitochondrial activities. The fact that atovaquone-resist ant mutants are hypersensitive to clindamycin, a drug believed to work on the putative plastid of these parasites, suggests a model for how the mitochondrion and plastid interact and how they may be tied into t he process and state of differentiation, This model is presented and d iscussed.