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

Kirsten Nielsen,^1,2 Gary M. Cox,^1,3 Ping Wang,^1, Dena L. Toffaletti,³ John R. Perfect,^1,3 and Joseph Heitman^1,2,3,4*

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 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 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 mating type serotype A strains. Virulence tests with rabbit and murine models of cryptococcal meningitis showed that the serotype A congenic a and mating type strains had equivalent virulence in animal models, in contrast to previous studies linking the 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.

Editor: T. R. Kozel

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

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