Toxoplasma gondii hsp90 is a potential drug target whose expression and subcellular localization are developmentally regulated

ECHEVERRIA P C; MATRAJT M,; HARB O S; ZAPPIA M P; MONICA ALEJANDRA COSTAS; ROOS D S; DUBREMETZ J F; ANGEL S O

J. Mol. Biol.

Año: 2005 vol. 350 p. 723 - 734

Two replicative forms characterize the asexual cycle of the protozoan parasite Toxoplasma gondii: rapidly growing tachyzoites and slowly dividing encysted bradyzoites. The mechanisms that regulate the transition between these two stages are not clearly understood. However, stress inducers that also activate heat shock protein expression can trigger formation of bradyzoites in vitro. Here we assessed the role of the T. gondii Hsp90 in modulating parasite differentiation and response to stress stimuli using RH ?UPRT parasites and the cystogenic strains PK and ME49. Our results show a strong increase in both the Hsp90 transcript and protein levels under stress or bradyzoite differentiation conditions. Moreover, fluorescence microscopy studies revealed that Hsp90 is present in the cytosol of tachyzoites and both in the nucleus and cytosol of mature bradyzoites, suggesting a correlation between its subcellular organization and these two developmental stages. To confirm a role for Hsp90 in bradyzoite differentiation, T. gondii tachyzoite mutants that are defective in differentiation showed the same staining pattern as tachyzoites under differentiation conditions. In addition, Geldanamycin (GA), a benzoquinone ansamycin antibiotic capable of binding and disrupting the function of Hsp90, blocked conversion both from the tachyzoite to bradyzoite and the bradyzoite to tachyzoite stage, suggesting an essential role for this protein in the regulation of stage interconversion. These results also implicate Hsp90 as a potential drug target in particular in potentially controlling reactivation of chronic toxoplasmosis in immunocompromised individuals.