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J. Biol. Chem., Vol. 278, Issue 42, 40757-40763, October 17, 2003

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Evidence That Intracellular 1-2 Mannan Is a Virulence Factor in Leishmania Parasites^*

Julie E. Ralton , Thomas Naderer , Helena L. Piraino, Tanya A. Bashtannyk, Judy M. Callaghan and Malcolm J. McConville, A Howard Hughes International Research Fellow. 

From the Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia

The protozoan parasite Leishmania mexicana proliferates within macrophage phagolysosomes in the mammalian host. In this study we provide evidence that a novel class of intracellular 1-2 mannan oligosaccharides is important for parasite survival in host macrophages. Mannan (degree of polymerization 4-40) is expressed at low levels in non-pathogenic promastigote stages but constitutes 80 and 90% of the cellular carbohydrate in the two developmental stages that infect macrophages, non-dividing promastigotes, and lesion-derived amastigotes, respectively. Mannan is catabolized when parasites are starved of glucose, suggesting a reserve function, and developmental stages having low mannan levels or L. mexicana GDPMP mutants lacking all mannose molecules are highly sensitive to glucose starvation. Environmental stresses, such as mild heat shock or the heat shock protein-90 inhibitor, geldanamycin, that trigger the differentiation of promastigotes to amastigotes, result in a 10-25-fold increase in mannan levels. Developmental stages with low mannan levels or L. mexicana mutants lacking mannan do not survive heat shock and are unable to differentiate to amastigotes or infect macrophages in vitro. In contrast, a L. mexicana mutant deficient only in components of the mannose-rich surface glycocalyx differentiates normally and infects macrophages in vitro. Collectively, these data provide strong evidence that mannan accumulation is important for parasite differentiation and survival in macrophages.

Received for publication, July 16, 2003 , and in revised form, August 4, 2003.

^* This work was supported by the Australian National Health and Medical Research Council, and equipment grants from the Wellcome Trust. 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 61-3-8344-5681; Fax: 61-3-9347-7730; E-mail: malcolmm{at}unimelb.edu.au.

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