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ORIGINAL ARTICLE

Identification and Role of Thiols in Toxoplasma gondii Egress

Elijah W. Stommel^*, Eunsung Cho, Jean Alex Steide, Rosanne Seguin, Aaron Barchowsky^§, Joseph D. Schwartzman^¶ and Lloyd H. Kasper^*,

^* Departments of Medicine (Section of Neurology),
Microbiology,
^§ Pharmacology, and
^¶ Pathology, Dartmouth Medical School, Lebanon, New Hampshire 03756; and
Neuroimmunology Unit, Montreal Neurological Institute, 3801 University, Montreal, QuebecH3A2B4,Canada

The nucleoside triphosphate hydrolase of Toxoplasma gondii is a potent apyrase that is secreted into the parasitophorous vacuole where it appears to be essentially inactive in an oxidized form. Recent evidence shows that nucleoside triphosphate hydrolase can be activated by dithiothreitol in vivo. On reduction of the enzyme, there is a rapid depletion of host cell ATP. Previous results also demonstrate a dithiothreitol induced egress of parasites from the host cell with a concurrent Ca²⁺ flux, postulated to be a consequence of the release of ATP-dependent Ca²⁺ stores within the tubulovesicular network of the parasitophorous vacuole. Reduction of the nucleoside triphosphate hydrolase appears crucial for its activation; however, the exact mechanism of reduction/activation has not been determined. Using a variety of techniques, we show here that glutathione promoters activate a Ca²⁺ flux and decrease ATP levels in infected human fibroblasts. We further show the in vitro activation of nucleoside triphosphate hydrolase by endogenous reducing agents, one of which we postulate might be secreted into the PV by T. gondii. Our findings suggest that the reduction of the parasite nucleoside triphosphate hydrolase, and ultimately parasite egress, is under the control of the parasites themselves.

Key Words: Toxoplasma gondii • Ca²⁺ • nucleoside triphosphate hydrolase • n-acetyl-cysteine • glutathione • glutathione s-transferase • glutaredoxin • thioredoxin

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