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Infection and Immunity, October 2000, p. 5668-5672, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Identification of Constituents of Human Neutrophil Azurophil Granules That Mediate Fungistasis against Histoplasma capsulatum

Simon L. Newman,1,* Lisa Gootee,1 Joelle E. Gabay,2 and Michael E. Selsted3

Department of Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio 452671; the Beatrice and Samuel A. Seaver Laboratory, Division of Hematology-Oncology, Department of Medicine, Cornell University Medical College, New York, New York 100212; and Department of Pathology, University of California---Irvine, College of Medicine, Irvine, California 926973

Received 6 March 2000/Returned for modification 11 April 2000/Accepted 29 June 2000

Previously we demonstrated that human neutrophils mediate potent and long-lasting fungistasis against Histoplasma capsulatum yeasts and that all of the fungistatic activity resides in the azurophil granules. In the present study, specific azurophil granule constituents with fungistatic activity were identified by incubation with H. capsulatum yeasts for 24 h and by quantifying the subsequent growth of yeasts via the incorporation of [3H]leucine. Human neutrophil defensins HNP-1, HNP-2, and HNP-3 inhibited the growth of H. capsulatum yeasts in a concentration-dependent manner with maximum inhibition at 8 µg/ml. At a concentration of 4 µg/ml, all possible paired combinations of defensins exhibited additive fungistatic activity against H. capsulatum yeasts. Cathepsin G and bactericidal-permeability-increasing protein (BPI) also mediated fungistasis against H. capsulatum in a concentration-dependent manner. The fungistatic activities of combinations of cathepsin G and BPI were additive, as were those of combinations of cathepsin G or BPI with HNP-1, HNP-2, and HNP-3. Lysozyme and elastase exhibited modest antifungal activity, and azurocidin and proteinase 3 exhibited no significant fungistasis against H. capsulatum yeasts. Thus, defensins, cathepsin G, and BPI are the major anti-H. capsulatum effector molecules in the azurophil granules of human neutrophils.

* Corresponding author. Mailing address: Division of Infectious Diseases, University of Cincinnati College of Medicine, P.O. Box 670560, Cincinnati, OH 45267. Phone: (513) 558-4704. Fax: (513) 558-2089. E-mail: newmansl{at}emailuc.edu.

Infection and Immunity, October 2000, p. 5668-5672, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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