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Infection and Immunity, October 2006, p. 5977-5988, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00768-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Cryptococcal Enzyme Inositol Phosphosphingolipid-Phospholipase C Confers Resistance to the Antifungal Effects of Macrophages and Promotes Fungal Dissemination to the Central Nervous System{dagger}

John M. Shea,1 Talar B. Kechichian,1 Chiara Luberto,1 and Maurizio Del Poeta1,2*

Departments of Biochemistry and Molecular Biology,1 Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 294252

Received 12 May 2006/ Returned for modification 16 June 2006/ Accepted 24 July 2006

In recent years, sphingolipids have emerged as critical molecules in the regulation of microbial pathogenesis. In fungi, the synthesis of complex sphingolipids is important for the regulation of pathogenicity, but the role of sphingolipid degradation in fungal virulence is not known. Here, we isolated and characterized the inositol phosphosphingolipid-phospholipase C1 (ISC1) gene from the fungal pathogen Cryptococcus neoformans and showed that it encodes an enzyme that metabolizes fungal inositol sphingolipids. Isc1 protects C. neoformans from acidic, oxidative, and nitrosative stresses, which are encountered by the fungus in the phagolysosomes of activated macrophages, through a Pma1-dependent mechanism(s). In an immunocompetent mouse model, the C. neoformans {Delta}isc1 mutant strain is almost exclusively found extracellularly and in a hyperencapsulated form, and its dissemination to the brain is remarkably reduced compared to that of control strains. Interestingly, the dissemination of the C. neoformans {Delta}isc1 strain to the brain is promptly restored in these mice when alveolar macrophages are pharmacologically depleted or when infecting an immunodeficient mouse in which macrophages are not efficiently activated. These studies suggest that Isc1 plays a key role in protecting C. neoformans from the intracellular environment of macrophages, whose activation is important for preventing fungal dissemination of the {Delta}isc1 strain to the central nervous system and the development of meningoencephalitis.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, BSB 503, Charleston, SC 29425. Phone: (843) 792-8381. Fax: (843) 792-8565. E-mail: delpoeta{at}musc.edu.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. Casadevall

Infection and Immunity, October 2006, p. 5977-5988, Vol. 74, No. 10
0019-9567/06/$08.00+0     doi:10.1128/IAI.00768-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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