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Infection and Immunity, September 2002, p. 5124-5131, Vol. 70, No. 9
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.9.5124-5131.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Histoplasma capsulatum Synthesizes Melanin-Like Pigments In Vitro and during Mammalian Infection

Joshua D. Nosanchuk,1* Beatriz L. Gómez,2,3 Sirida Youngchim,2,4 Soraya Díez,2,3 Philip Aisen,5 Rosely M. Zancopé-Oliveira,6 Angela Restrepo,3 Arturo Casadevall,1,7 and Andrew J. Hamilton2

Departments of Medicine,1 Physiology and Biophysics,5 Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York,7 Dermatology Department, St. Johns Institute of Dermatology, Guy's Hospital, Guy's, Kings, and St. Thomas Medical Schools, London, United Kingdom,2 Corporación para Investigaciones Biológicas, Medellín, Colombia,3 Microbiology Department, Chiang-Mai Medical School, Chiang-Mai, Thailand,4 Centro de Pesquisas Hospital Evandro Chagas, Fundacao Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil6

Received 22 January 2002/ Returned for modification 21 March 2002/ Accepted 6 June 2002

Melanin is made by several important pathogenic fungi and has been implicated in the pathogenesis of a number of fungal infections. This study investigated whether the thermally dimorphic fungal pathogen Histoplasma capsulatum var. capsulatum produced melanin or melanin-like compounds in vitro and during infection. Growth of H. capsulatum mycelia in chemically defined minimal medium produced pigmented conidia. Growth of H. capsulatum yeast in chemically defined minimal medium with L-3,4-dihydroxyphenylalanine (DOPA) or (-)-epinephrine produced pigmented cells. Treatment of the pigmented cells with proteolytic enzymes, denaturant, and hot concentrated acid yielded dark particles that were similar in size and shape to their respective propagules. Melanin-binding monoclonal antibodies (MAb) labeled pigmented conidia, yeast, and the isolated particles as determined by immunofluorescence microscopy. Electron spin resonance spectroscopy revealed that pigmented yeast cells and particles derived from pigmented cells were stable free radicals consistent with their identification as melanins. Tissues from mice infected with H. capsulatum and from biopsy specimens from a patient with histoplasmosis contained fungal cells that were labeled by melanin-binding MAb. Digestion of infected mouse tissues yielded dark particles that reacted with the melanin-binding MAb and were similar in appearance to H. capsulatum yeast cells. Additionally, sera from infected mice contained antibodies that bound melanin particles. Phenoloxidase activity capable of synthesizing melanin from L-DOPA was detected in cytoplasmic yeast cell extracts. These findings indicate that H. capsulatum conidia and yeast can produce melanin or melanin-like compounds in vitro and that yeast cells can synthesize pigment in vivo. Since melanin is an important virulence factor in other pathogenic fungi, this pigment may have a similar role to play in the pathogenesis of histoplasmosis.

* Corresponding author. Mailing address: Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-3766. Fax: (718) 430-8701. E-mail: nosanchu{at}aecom.yu.edu.

Editor: T. R. Kozel

Infection and Immunity, September 2002, p. 5124-5131, Vol. 70, No. 9
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.9.5124-5131.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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