Interconnection between organellar functions, development and drug resistance in the protozoan parasite, Toxoplasma gondii.
The protozoan parasite Toxoplasma gondii causes severe disease in animals and humans. In AIDS patients, for example, the encephalitis it produces is a major cause of death. Part of the very successful strategy adopted by the parasite centers on its ability to differentiate from the actively growing tachyzoite form to a chronic, almost latent state called the bradyzoite. The molecular signals and precise triggers involved in this differentiation process are not known. Drugs for treating toxoplasmosis are not capable of clearing the infection apparently because of their inability to eradicate the bradyzoites. Recently, as part of our efforts to understand the mode of action of a promising new drug, atovaquone, we have generated and analysed a mutant that is resistant to this drug. Surprisingly, we found that this mutant is predisposed to spontaneously differentiate from the tachyzoite to bradyzoite form in vitro (Tomavo & Boothroyd, submitted). Given that atovaquone is believed to act on the parasite mitochondria, we were interested to explore the relationship between mitochondrial function and differentiation. We find that atovaquone and a number of other drugs targeted to mitochondria will cause wild type parasites to differentiate from tachyzoites to bradyzoites suggesting some sort of adaptive response to a decrease in mitochondrial activities. The fact that atovaquone-resistant 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 the process and state of differentiation. This model is presented and discussed.
Tomavo
S
S
Department of Microbiology and Immunology, Stanford University School of Medicine, CA 94305-5402, USA.
Boothroyd
J C
JC
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000469:parasitology; D000818:Animals; D000953:Antigens, Protozoan / Q000096:biosynthesis* / Q000302:isolation & purification; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004272:DNA, Mitochondrial / Q000378:metabolism; D018432:Drug Resistance, Multiple; D005347:Fibroblasts; D015870:Gene Expression; D017125:Genes, Protozoan; D006801:Humans; D015388:Organelles / Q000187:drug effects / Q000502:physiology; D014122:Toxoplasma / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D014123:Toxoplasmosis / Q000188:drug therapy; D014124:Toxoplasmosis, Animal / Q000188:drug therapy; D014709:Vero Cells
D000953:Antigens, Protozoan; D000981:Antiprotozoal Agents; D004272:DNA, Mitochondrial