Laccase of Cryptococcus neoformans Is a Cell Wall-Associated Virulence Factor

doi:10.1128/IAI.69.9.5589-5596.2001

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Infection and Immunity, September 2001, p. 5589-5596, Vol. 69, No. 9
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.9.5589-5596.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Laccase of Cryptococcus neoformans Is a Cell Wall-Associated Virulence Factor

Xudong Zhu,¹ Jack Gibbons,² Javier Garcia-Rivera,³ Arturo Casadevall,⁴ and Peter R. Williamson¹^,^*

Division of Infectious Diseases, University of Illinois at Chicago College of Medicine,¹ Division of Biological Sciences, University of Illinois at Chicago,² Chicago, Illinois, and Department of Microbiology and Immunology³ and Division of Infectious Diseases,⁴ Albert Einstein College of Medicine, Bronx, New York

Received 9 May 2001/Returned for modification 11 June 2001/Accepted 20 June 2001

Virulence is the outcome of an interaction between the host and a microbe and is characterized by a large array of opposingreactions operating at the host-pathogen interface. Cryptococcusneoformans is an important opportunistic pathogen in immunocompromisedpatients, including those with human immunodeficiency virus, andexpresses a virulence-associated laccase which is believed tooxidize brain catecholamines and iron as a defense against hostimmune cells. In the present report, we investigated the cellularlocation of laccase to understand more fully how it contributesto cryptococcal virulence. A monoclonal antibody to the C. neoformanslaccase was generated and used to show localization in the cellwalls of representative serotype A (H99) and serotype D (B-3501)strains by immunoelectron microscopy. In addition, confocal microscopywas used to show a peripheral location of green fluorescent protein-taggedlaccase expressed in live H99 cells. Biochemical studies showedthat laccase could be released from intact cells or cell wallfractions with glucanase enzymes but was retained in the cellwall after sequential extraction with 1 M NaCl, 6 M urea, and1% sodium dodecyl sulfate. The presence of a hydrolyzable bondlinking laccase to the cell wall was suggested by removal of laccasefrom cell wall preparations after they were boiled in 1% sodiumdodecyl sulfate, as was the presence of a disulfide or thioesterbond by removal with dithiothreitol or $beta$ -mercaptoethanol. Thesedata show that laccase is present as a tightly associated cellwall enzyme that is readily accessible for interactions with hostimmunecells.

^* Corresponding author. Mailing address: Rm. 888, m/c 735, 808 S. Wood St., Chicago, IL 60612. Phone: (312) 996-6070. Fax: (312)996-5704. E-mail: prw{at}uic.edu.

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