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Infection and Immunity, June 2004, p. 3622-3627, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3622-3627.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Identification of a Compensatory Mutant (lpg2^–REV) of Leishmania major Able To Survive as Amastigotes within Macrophages without LPG2-Dependent Glycoconjugates and Its Significance to Virulence and Immunization Strategies

Gerald F. Späth,^1, Lon-Fye Lye,¹ Hiroaki Segawa,² Salvatore J. Turco,² and Stephen M. Beverley^1*

Department of Molecular Microbiology, Washington University Medical School, St. Louis, Missouri 63110,¹ Department of Biochemistry, University of Kentucky Medical School, Lexington, Kentucky 40536²

Received 24 December 2003/ Returned for modification 7 February 2004/ Accepted 2 March 2004

Different Leishmania species rely to different extents on abundant glycoconjugates, such as lipophosphoglycan (LPG) and related molecules, in mammalian infections. Previously, we showed that Leishmania major deletion mutants lacking the Golgi GDP-mannose transporter LPG2, which is required for assembly of the dominant phosphoglycan (PG) repeats of LPG, were unable to survive in macrophages. These lpg2^– mutants, however, retained the ability to generate asymptomatic, persistent infections in mice. In contrast, Ilg and colleagues showed that Leishmania mexicana LPG2 mutants retained virulence for mice. Here we identified a partial revertant population of the L. major lpg2^– mutants (designated lpg2^–REV) that had regained the ability to replicate in macrophages and induce disease pathology through a compensatory change. Like the lpg2 parent, the lpg2^–REV revertant was unable to synthesize LPG2-dependent PGs in the promastigote stage and thus remained highly attenuated in the ability to induce infection. However, after considerable delay lpg2^–REV revertant-infected mice exhibited lesions, and amastigotes isolated from these lesions were able to replicate within macrophages despite the fact that they were unable to synthesize PGs. Thus, in some respects, the lpg2^–REV amastigotes resemble L. mexicana amastigotes. Future studies of the gene(s) responsible may shed light on the mechanisms employed by L. major to survive in the absence of LPG2-dependent glycoconjugates and may also improve the potential of the lpg2^– L. major line to serve as a live parasite vaccine by overcoming its tendency to revert toward virulence.

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* Corresponding author. Mailing address: Department of Molecular Microbiology, Washington University Medical School, Campus Box 8230, 660 S. Euclid Ave., St. Louis, MO 63110. Phone: (314) 747-2630. Fax: (314) 747-2634. E-mail: beverley{at}borcim.wustl.edu.

Editor: W. A. Petri, Jr.

Present address: Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, NY 10010.

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Infection and Immunity, June 2004, p. 3622-3627, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3622-3627.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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