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J. Biol. Chem., Vol. 280, Issue 16, 16345-16353, April 22, 2005

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Selective Disruption of Phosphatidylcholine Metabolism of the Intracellular Parasite Toxoplasma gondii Arrests Its Growth^*

Nishith Gupta, Matthew M. Zahn, Isabelle Coppens, Keith A. Joiner¶, and Dennis R. Voelker||

From the Program in Cell Biology, Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80206, the Blomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland 21205, and the ^¶Section of Infectious Diseases, Investigative Medicine Program, Yale University School of Medicine, New Haven, Connecticut 06520

Toxoplasma gondii is an intracellular protozoan parasite capable of causing devastating infections in immunocompromised and immunologically immature individuals. In this report, we demonstrate the relative independence of T. gondii from its host cell for aminoglycerophospholipid synthesis. The parasite can acquire the lipid precursors serine, ethanolamine, and choline from its environment and use them for the synthesis of its major lipids, phosphatidylserine (PtdSer), phosphatidylethanolamine (PtdEtn), and phosphatidylcholine (PtdCho), respectively. Dimethylethanolamine (Etn(Me)₂), a choline analog, dramatically interfered with the PtdCho metabolism of T. gondii and caused a marked inhibition of its growth within human foreskin fibroblasts. In tissue culture medium supplemented with 2 mM Etn(Me)₂, the parasite-induced lysis of the host cells was dramatically attenuated, and the production of parasites was inhibited by more than 99%. The disruption of parasite growth was paralleled by structural abnormalities in its membranes. In contrast, no negative effect on host cell growth and morphology was observed. The data also reveal that the Etn(Me)₂-supplemented parasite had a time-dependent decrease in its PtdCho content and an equivalent increase in phosphatidyldimethylethanolamine, whereas other major lipids, PtdSer, PtdEtn, and PtdIns, remained largely unchanged. Relative to host cells, the parasites incorporated more than 7 times as much Etn(Me)₂ into their phospholipid. These findings reveal that Etn(Me)₂ selectively alters parasite lipid metabolism and demonstrate how selective inhibition of PtdCho synthesis is a powerful approach to arresting parasite growth.

Received for publication, February 9, 2005

^* This work was supported by National Institutes of Health Research Grants AI030060 (to K. A. J. and D. R. V.) and 2R37GM32453 (to D. R. V.). 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: Program in Cell Biology, Dept. of Medicine, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Tel.: 303-398-1300; Fax: 303-398-1806; E-mail: voelkerd{at}njc.org.

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