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Infection and Immunity, February 2000, p. 443-448, Vol. 68, No. 2
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Urease as a Virulence Factor in Experimental Cryptococcosis

Gary M. Cox,1,* Jean Mukherjee,2 Garry T. Cole,3 Arturo Casadevall,2 and John R. Perfect1

Division of Infectious Disease, Department of Medicine, Duke University Medical Center, Durham, North Carolina 277101; Division of Infectious Diseases, Department of Medicine, and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 104612; and Department of Microbiology and Immunology, Medical College of Ohio, Toledo, Ohio 436143

Received 18 June 1999/Returned for modification 6 August 1999/Accepted 8 November 1999

Urease catalyzes the hydrolysis of urea to ammonia and carbamate and has been found to be an important pathogenic factor for certain bacteria. Cryptococcus neoformans is a significant human pathogenic fungus that produces large amounts of urease; thus we wanted to investigate the importance of urease in the pathogenesis of cryptococcosis. We cloned and sequenced the genomic locus containing the single-copy C. neoformans urease gene (URE1) and used this to disrupt the native URE1 in the serotype A strain H99. The ure1 mutant strains were found to have in vitro growth characteristics, phenoloxidase activity, and capsule size similar to those of the wild type. Comparison of a ure1 mutant with H99 after intracisternal inoculation into corticosteroid-treated rabbits revealed no significant differences in colony counts recovered from the cerebrospinal fluid. However, when these two strains were compared in both the murine intravenous and inhalational infection models, there were significant differences in survival. Mice infected with a ure1 strain lived longer than mice infected with H99 in both models. The ure1 strain was restored to urease positivity by complementation with URE1, and two resulting transformants were significantly more pathogenic than the ure1 strain. Our results suggest that urease activity is involved in the pathogenesis of cryptococcosis but that the importance may be species and/or infection site specific.

* Corresponding author. Mailing address: Box 3353, Duke Medical Center, Durham, NC 27710. Phone: (919) 681-5055. Fax: (919) 684-8902. E-mail: cox00005{at}mc.duke.edu.

Infection and Immunity, February 2000, p. 443-448, Vol. 68, No. 2
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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