Sexual cycle of Cryptococcus neoformans var. grubii and virulence of congenic a and alpha isolates

Infect Immun. 2003 Sep;71(9):4831-41. doi: 10.1128/iai.71.9.4831-4841.2003.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Cryptococcus neoformans / genetics
  • Cryptococcus neoformans / isolation & purification
  • Cryptococcus neoformans / pathogenicity*
  • Cryptococcus neoformans / physiology*
  • DNA, Fungal / genetics
  • Female
  • Genes, Fungal
  • Genes, Mating Type, Fungal
  • Haploidy
  • Humans
  • Male
  • Meningitis, Cryptococcal / etiology
  • Meningitis, Cryptococcal / microbiology
  • Mice
  • Mice, Inbred A
  • Molecular Sequence Data
  • Mutation
  • Opportunistic Infections / etiology
  • Opportunistic Infections / microbiology
  • Rabbits
  • Recombination, Genetic
  • Serotyping
  • Virulence / genetics

Substances

  • DNA, Fungal

Associated data

  • GENBANK/AY219893
  • GENBANK/AY219894
  • GENBANK/AY219895
  • GENBANK/AY219896