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Infection and Immunity, October 2006, p. 5877-5887, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00624-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Characterization and Regulation of the Trehalose Synthesis Pathway and Its Importance in the Pathogenicity of Cryptococcus neoformans

Elizabeth Wills Petzold,¹ Uwe Himmelreich,^2, Eleftherios Mylonakis,³ Thomas Rude,¹ Dena Toffaletti,¹ Gary M. Cox,¹ Jackie L. Miller,¹ and John R. Perfect^1*

Department of Medicine, Duke University Medical Center, Durham, North Carolina,¹ Center for Infectious Diseases and Microbiology and Westmead Millennium Institute, University of Sydney, Sydney, Australia,² Massachusetts General Hospital, Boston, Massachusetts³

Received 18 April 2006/ Returned for modification 3 June 2006/ Accepted 22 July 2006

The disaccharide trehalose has been found to play diverse roles, from energy source to stress protectant, and this sugar is found in organisms as diverse as bacteria, fungi, plants, and invertebrates but not in mammals. Recent studies in the pathobiology of Cryptococcus neoformans identified the presence of a functioning trehalose pathway during infection and suggested its importance for C. neoformans survival in the host. Therefore, in C. neoformans we created null mutants of the trehalose-6-phosphate (T6P) synthase (TPS1), trehalose-6-phophate phosphatase (TPS2), and neutral trehalase (NTH1) genes. We found that both TPS1 and TPS2 are required for high-temperature (37°C) growth and glycolysis but that the block at TPS2 results in the apparent toxic accumulation of T6P, which makes this enzyme a fungicidal target. Sorbitol suppresses the growth defect in the tps1 and tps2 mutants at 37°C, which supports the hypothesis that these sugars (trehalose and sorbitol) act primarily as stress protectants for proteins and membranes during exposure to high temperatures in C. neoformans. The essential nature of this pathway for disease was confirmed when a tps1 mutant strain was found to be avirulent in both rabbits and mice. Furthermore, in the system of the invertebrate C. elegans, in which high in vivo temperature is no longer an environmental factor, attenuation in virulence was still noted with the tps1 mutant, and this supports the hypothesis that the trehalose pathway in C. neoformans is involved in more host survival mechanisms than simply high-temperature stresses and glycolysis. These studies in C. neoformans and previous studies in other pathogenic fungi support the view of the trehalose pathway as a selective fungicidal target for use in antifungal development.

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* Corresponding author. Mailing address: P.O. Box 3353, Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-4016. Fax: (919) 684-8902. E-mail: perfe001{at}mc.duke.edu.

Editor: A. Casadevall

Present address: Max Planck Institute for Neurological Research, Cologne, Germany.

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Infection and Immunity, October 2006, p. 5877-5887, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00624-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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