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J. Biol. Chem., Vol. 279, Issue 50, 52300-52311, December 10, 2004

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The Expression of Lactate Dehydrogenase Is Important for the Cell Cycle of Toxoplasma gondii^*

Fatme Al-Anouti, Stanislas Tomavo, Stephen Parmley¶, and Sirinart Ananvoranich||

From the Chemistry and Biochemistry Department, University of Windsor, Windsor, Ontario N9B 3P4, Canada, Equipe de Parasitologie Moléculaire, Laboratoire de Chimie Biologique, UGSF, CNRS UMR 8576, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq, France, and ^¶Department of Immunology and Infectious Diseases, Palo Alto Medical Foundation, Palo Alto, California 94305

In Toxoplasma gondii, lactate dehydrogenase is encoded by two independent and developmentally regulated genes LDH1 and LDH2. These genes and their products have been implicated in the control of a metabolic flux during parasite differentiation. To investigate the significance of LDH1 and LDH2 in this process, we generated stable transgenic parasite lines in which the expression of these two expressed isoforms of lactate dehydrogenase was knocked down in a stage-specific manner. These LDH knockdown parasites exhibited variable growth rates in either the tachyzoite or the bradyzoite stage, as compared with the parental parasites. Their differentiation processes were impaired when the parasites were grown under in vitro conditions. In vivo studies in a murine model system revealed that tachyzoites of these parasite lines were unable to form significant numbers of tissue cysts and to establish a chronic infection. Most importantly, all mice that were initially infected with tachyzoites of either of the four LDH knockdown lines survived a subsequent challenge with tachyzoites of the parental parasites (10⁴), a dose that usually causes 100% mortality, suggesting that live vaccination of mice with the LDH knockdown tachyzoites can confer protection against T. gondii. Thus, we conclude that LDH expression is essential for parasite differentiation. The knockdown of LDH1 and LDH2 expression gave rise to virulence-attenuated parasites that were unable to exhibit a significant brain cyst burden in a murine model of chronic infection.

Received for publication, August 11, 2004 , and in revised form, September 30, 2004.

^* This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (to S. A.), the Ministry of Colleges and Universities of Ontario (to F. A.), and the CNRS (to S. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 519-253-3000 (ext. 3550); Fax: 519-973-7098; E-mail: anans{at}uwindsor.ca.

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