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Infection and Immunity, March 2004, p. 1693-1699, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1693-1699.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

CNLAC1 Is Required for Extrapulmonary Dissemination of Cryptococcus neoformans but Not Pulmonary Persistence

Mairi C. Noverr,1,2 Peter R. Williamson,3 Ryan S. Fajardo,1 and Gary B. Huffnagle1,2*

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine,1 Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109,2 Division of Infectious Diseases, University of Illinois at Chicago College of Medicine, Chicago, Illinois 606123

Received 22 July 2003/ Returned for modification 26 August 2003/ Accepted 19 November 2003

The pathogenic yeast Cryptococcus neoformans produces a laccase enzyme (CNLAC1), which catalyzes the synthesis of melanin in the presence of phenolic compounds. A number of genes have been implicated in the regulation of laccase and melanization, including IPC1, GPA1, MET3, and STE12. Albino mutants derived from random mutagenesis techniques may contain mutations in genes that regulate multiple virulence factors, including CNLAC1. The goal of our study is to investigate the role of CNLAC1 in virulence and evasion of pulmonary host defenses after infection via the respiratory tract. Using a set of congenic laccase-positive (2E-TUC-4) and laccase-deficient (2E-TU-4) strains, we found that both strains are avirulent at a lower dose (104 CFU/mouse) in mice. After the infectious dose was increased to 106 CFU/mouse, 70% mortality was observed in mice infected with 2E-TUC-4 compared to no mortality in mice infected with 2E-TU-4 at day 30 postinfection. This observation confirms the requirement for CNLAC1 in virulence. Interestingly, we observed no differences between the two strains in pulmonary growth or in elicitation of cellular immune responses in the lung. The only measurable defect of 2E-TU-4 was in dissemination to extrapulmonary sites. To examine the role of CNLAC1 in dissemination, mice were infected intravenously. By week 3 postinfection, equal numbers of strains 2E-TUC-4 and 2E-TU-4 were recovered from the brain and spleen. This observation indicates that CNLAC1 facilitates escape from the lung, but not growth in the lungs or brain, and suggests a novel role for CNLAC1 in virulence during an infection aquired via the respiratory tract.

* Corresponding author. Mailing address: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0642. Phone: (734) 936-9368. Fax: (734) 764-4556. E-mail: ghuff{at}umich.edu.

Editor: T. R. Kozel

Infection and Immunity, March 2004, p. 1693-1699, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1693-1699.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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