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Infection and Immunity, October 2008, p. 4764-4771, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.00660-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Cryptococcus neoformans Enters the Endolysosomal Pathway of Dendritic Cells and Is Killed by Lysosomal Components{triangledown} ,{dagger}

Karen L. Wozniak and Stuart M. Levitz*

Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, Massachusetts

Received 28 May 2008/ Returned for modification 2 July 2008/ Accepted 21 July 2008

Cryptococcus neoformans is an opportunistic fungal pathogen that primarily causes disease in immunocompromised individuals. Dendritic cells (DCs) can phagocytose C. neoformans, present cryptococcal antigen, and kill C. neoformans. However, early events following C. neoformans phagocytosis by DCs are not well defined. We hypothesized that C. neoformans traffics to the endosome and the lysosome following phagocytosis by DCs and is eventually killed in the lysosome. Murine bone marrow-derived DCs (BMDCs) or human monocyte-derived DCs (HDCs) were incubated with live, encapsulated C. neoformans yeast cells and opsonizing antibody. Following incubation, DCs were intracellularly stained with antibodies against EEA1 (endosome) and LAMP-1 (late endosome/lysosome). As assessed by confocal microscopy, C. neoformans trafficked to endosomal compartments of DCs within 10 min and to lysosomal compartments within 30 min postincubation. For HDCs, the studies were repeated using complement-sufficient autologous plasma for the opsonization of C. neoformans. These data showed results similar to those for antibody opsonization, with C. neoformans localized to endosomes within 20 min and to lysosomes within 60 min postincubation. Additionally, the results of live real-time imaging studies demonstrated that C. neoformans entered lysosomal compartments within 20 min following the initiation of phagocytosis. The results of scanning and transmission electron microscopy demonstrated conventional zipper phagocytosis of C. neoformans by DCs. Finally, lysosomal extracts were purified from BMDCs and incubated with C. neoformans to determine their potential to kill C. neoformans. The extracts killed C. neoformans in a dose-dependent manner. This study shows that C. neoformans enters into endosomal and lysosomal pathways following DC phagocytosis and can be killed by lysosomal components.

* Corresponding author. Mailing address: Department of Medicine, Division of Infectious Diseases, 364 Plantation St., LRB317, University of Massachusetts Medical School, Worcester, MA 01605. Phone: (508) 856-1525. Fax: (508) 856-1828. E-mail: Stuart.Levitz{at}umassmed.edu

{triangledown} Published ahead of print on 4 August 2008.

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

Editor: A. Casadevall

Infection and Immunity, October 2008, p. 4764-4771, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.00660-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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