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J. Biol. Chem., Vol. 278, Issue 45, 44708-44718, November 7, 2003

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Ether Phospholipids and Glycosylinositolphospholipids Are Not Required for Amastigote Virulence or for Inhibition of Macrophage Activation by Leishmania major^*

Rachel Zufferey, Simon Allen¶||, Tamara Barron**, Deborah R. Sullivan**, Paul W. Denny, Igor C. Almeida, Deborah F. Smith, Salvatore J. Turco**, Michael A. J. Ferguson¶, and Stephen M. Beverley¶¶

From the Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110, the ^¶Wellcome Trust Biocentre, University of Dundee, Dundee DD1 4HN, Scotland, United Kingdom, the ^**Department of Biochemistry, University of Kentucky Medical Center, Lexington, Kentucky 45306, the Department of Biological Sciences, Wellcome Trust Laboratories for Molecular Parasitology, Imperial College, London SW7 1AZ, United Kingdom, and the Department of Parasitology, Universidade de Sao Paulo, Sao Paulo 05508-900, Brazil

Ether phospholipids are major components of the membranes of humans and Leishmania. In protozoan parasites they occur separately or as part of the glycosylphosphatidylinositol (GPI) anchor of molecules implicated in virulence, such as lipophosphoglycan (LPG), smaller glycosylinositolphospholipids (GIPLs), and GPI-anchored proteins. We generated null mutants of the Leishmania major alkyldihydroxyacetonephosphate synthase (ADS), the first committed step of ether lipid synthesis. Enzymatic analysis and comprehensive mass spectrometric analysis showed that ads1^- knock-outs lacked all ether phospholipids, including plasmalogens, LPG, and GIPLs. Leishmania ads1^- thus represents the first ether lipid-synthesizing eukaryote for which a completely null mutant could be obtained. Remarkably ads1^- grew well and maintained lipid rafts (detergent-resistant membranes). In virulence tests it closely resembled LPG-deficient L. major, including sensitivity to complement and an inability to survive the initial phase of macrophage infection. Likewise it retained the ability to inhibit host cell signaling and to form infectious amastigotes from the few parasites surviving the establishment defect. These findings counter current proposals that GIPLs are required for amastigote survival in the mammalian host or that parasite lyso-alkyl or alkylacyl-GPI anchors are solely responsible for inhibition of macrophage activation.

Received for publication, July 24, 2003 , and in revised form, August 25, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY328521.

^* This work was supported by a Human Frontier Science Program Organization grant (to R. Z.), Wellcome Trust Program Grants 054491 and 061343 (to M. A. J. F. and D. F. S., respectively), a Biotechnology and Biological Sciences Research Council Ph.D. studentship (to S. A.), Conselho Nacional de Pesquisas (Brazil) Research Fellowship 98/10495-5 (to I. C. A.), and National Institutes of Health grants (to S. J. T. and S. M. B.). 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.

Present address: Dept. of Pathology and Center for Microbial Pathogenesis, University of Connecticut Health Center, Farmington, CT 06032.

^|| Present address: Buck Inst., 8001 Redwood Blvd., Novato, CA 94945.

^¶¶ To whom correspondence should be addressed: Dept. of Molecular Microbiology, Campus Box 8230, Washington University Medical School, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-747-2630; Fax: 314-747-2634; E-mail: beverley{at}borcim.wustl.edu.

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