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Infection and Immunity, September 2003, p. 4831-4841, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.4831-4841.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Sexual Cycle of Cryptococcus neoformans var. grubii and Virulence of Congenic a and {alpha} Isolates

Kirsten Nielsen,1,2 Gary M. Cox,1,3 Ping Wang,1,{dagger} Dena L. Toffaletti,3 John R. Perfect,1,3 and Joseph Heitman1,2,3,4*

Departments of Molecular Genetics and Microbiology,1 Medicine,3 Pharmacology and Cancer Biology,4 Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 277102

Received 21 March 2003/ Returned for modification 12 April 2003/ Accepted 28 April 2003

Cryptococcus neoformans is a human-pathogenic fungus that has evolved into three distinct varieties that infect most prominently the central nervous system. A sexual cycle involving haploid cells of a and {alpha} mating types has been reported for two varieties (C. neoformans var. neoformans, serotype D, and C. neoformans var. gattii, serotypes B and C), yet the vast majority of infections involve a distinct variety (C. neoformans var. grubii, serotype A) that has been thought to be clonal and restricted to the {alpha} mating type. We recently identified the first serotype A isolate of the a mating type which had been thought to be extinct (strain 125.91). Here we report that this unusual strain can mate with a subset of pathogenic serotype A strains to produce a filamentous dikaryon with fused clamp connections, basidia, and viable recombinant basidiospores. One meiotic segregant mated poorly with the serotype A reference strain H99 but robustly with a crg1 mutant that lacks a regulator of G protein signaling and is hyperresponsive to mating pheromone. This meiotic segregant was used to create congenic a and {alpha} mating type serotype A strains. Virulence tests with rabbit and murine models of cryptococcal meningitis showed that the serotype A congenic a and {alpha} mating type strains had equivalent virulence in animal models, in contrast to previous studies linking the {alpha} mating type to increased virulence in congenic serotype D strains. Our studies highlight a role for sexual recombination in the evolution of a human fungal pathogen and provide a robust genetic platform to establish the molecular determinants of virulence.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, 322 CARL Building, Research Dr., Duke University Medical Center, Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail: heitm001{at}duke.edu.

Editor: T. R. Kozel

{dagger} Present address: Department of Pediatrics and Microbiology, Children's Hospital, New Orleans, LA 70118.

Infection and Immunity, September 2003, p. 4831-4841, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.4831-4841.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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