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Infection and Immunity, October 2005, p. 6803-6811, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6803-6811.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Human Dendritic Cell Activity against Histoplasma capsulatum Is Mediated via Phagolysosomal Fusion

Lucy A. Gildea,1 Georgianne M. Ciraolo,2 Randal E. Morris,2 and Simon L. Newman1*

Department of Internal Medicine, Division of Infectious Diseases,1 Department of Anatomy, Cell Biology, and Neurobiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 452672

Received 6 May 2005/ Returned for modification 31 May 2005/ Accepted 22 June 2005

Histoplasma capsulatum is a fungal pathogen that requires the induction of cell-mediated immunity (CMI) for host survival. We have demonstrated that human dendritic cells (DC) phagocytose H. capsulatum yeasts and, unlike human macrophages (Mø) that are permissive for intracellular growth, DC killed and degraded the fungus. In the present study, we sought to determine whether the mechanism(s) by which DC kill Histoplasma is via lysosomal hydrolases, via the production of toxic oxygen metabolites, or both. Phagosome-lysosome fusion (PL-fusion) was quantified by using fluorescein isothiocyanate-dextran and phase and fluorescence microscopy and by electron microscopy with horseradish peroxidase colloidal gold to label lysosomes. Unlike M{phi}, Histoplasma-infected DC exhibited marked PL-fusion. The addition of suramin to Histoplasma-infected DC inhibited PL-fusion and DC fungicidal activity. Incubation of Histoplasma-infected DC at 18°C also concomitantly reduced PL-fusion and decreased the capacity of DC to kill and degrade H. capsulatum yeasts. Further, culture of Histoplasma-infected DC in the presence of bafilomycin, an inhibitor of the vacuolar ATPase, did not block DC anti-Histoplasma activity, indicating that phagosome acidification was not required for lysosome enzyme activity. In contrast, culture of Histoplasma-infected DC in the presence of inhibitors of the respiratory burst or inhibitors of NO synthase had little to no effect on DC fungicidal activity. These data suggest that the major mechanism by which human DC mediate anti-Histoplasma activity is through the exposure of yeasts to DC lysosomal hydrolases. Thus, DC can override one of the strategies used by H. capsulatum yeasts to survive intracellularly within Mø.

* Corresponding author. Mailing address: Division of Infectious Diseases, University of Cincinnati College of Medicine, P.O. Box 670560, Cincinnati, OH 45267-0560. Phone: (513) 558-4709. Fax: (513) 558-2089. E-mail: newmansl{at}email.uc.edu.

Editor: T. R. Kozel

Infection and Immunity, October 2005, p. 6803-6811, Vol. 73, No. 10
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.10.6803-6811.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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