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Deciphering the Model Pathogenic Fungus Cryptococcus Neoformans

Nature Reviews Microbiology volume 3, pages 753–764 (2005)Cite this article

Key Points

  • The Cryptococcus neoformans genome comprises 20 Mb of DNA over 14 chromosomes, encoding 6,574 predicted genes. Unusual features include high levels of alternatively spliced genes (4.3%) and antisense messages (0.8%).

  • The genome contains many predicted transposons (5% of nucleotide content), but these are inactive most of the time. Nevertheless, such repetitive elements enable genome rearrangements, both in small regions to cause inversions, such as in the mating-type locus, and in larger regions to cause DNA-duplication events across chromosomes.

  • Development of research tools (for genetics, targeted and random mutagenesis, gene expression profiling and virulence assays) makes C. neoformans the most amenable human pathogenic fungus to study.

  • The maintenance of virulence in the fungus depends on interactions with the environment, rather than the human host. Environmental hosts can include microorganisms like amoeba or nematodes, insects or small mammals.

  • It is still unclear whether humans are infected by C. neoformans yeast cells or sexual basidiospores. The fungus is heterothallic, but can also undergo sexual recombination between strains of a single mating-type identity, suggesting a means of generating spores in the absence of an opposite mating partner.

  • Mating-type specificity is controlled by a region of the genome (the MAT locus) that is unusually large (∼100 kb) compared with other fungi. Comparison of this sequence in three divergent strains suggests that the region evolved from the fusion of a tetrapolar mating system into a bipolar system.

  • The ability to sense and respond to the environment is mediated by signal-transduction pathways that are conserved between C. neoformans and other fungi; however, most of the upstream receptors and downstream transcriptional regulators are divergent, as is the crosstalk between the pathways. In addition, the genome contains many uncharacterized signal-transduction proteins.

Abstract

Cryptococcus neoformans is a basidiomycete fungal pathogen of humans that has diverged considerably from other model fungi such as Neurospora crassa, Aspergillus nidulans, Saccharomyces cerevisiae and the common human fungal pathogen Candida albicans. The recent completion of the genome sequences of two related C. neoformans strains and the ongoing genome sequencing of three other divergent Cryptococcus strains with different virulence phenotypes and environmental distributions should improve our understanding of this important pathogen. We discuss the biology of C. neoformans in light of this genomic data, with a special emphasis on the role that evolution and sexual reproduction have in the complex relationships of the fungus with the environment and the host.

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Figure 1: Distinguishing features of Cryptococcus neoformans.
Figure 2: The Cryptococcus neoformans genome.
Figure 3: Virulence pathway of Cryptococcus neoformans.
Figure 4: Model of the Cryptococcus neoformans life cycle.
Figure 5: Cryptococcus neoformans signal-transduction systems.

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Acknowledgements

We have regrettably been unable to include all papers featuring C. neoformans in this review, and apologize to those colleagues whose work we were unable to cover in detail. Research by the authors is supported by the Howard Hughes Medical Institute and the National Institutes of Health.

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Authors and Affiliations

  1. Department of Molecular Genetics and Microbiology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Alexander Idnurm, Yong-Sun Bahn, Kirsten Nielsen, Xiaorong Lin, James A. Fraser & Joseph Heitman

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  1. Alexander Idnurm
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  2. Yong-Sun Bahn
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  3. Kirsten Nielsen
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Correspondence to Joseph Heitman.

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Related links

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DATABASES

Entrez

Cryptococcus neoformans var. grubii H99

Cryptococcus neoformans var. neoformans B-3501A

Cryptococcus neoformans var. neoformans JEC21

Cryptococcus gattii R265

Cryptococcus gattii WM276

Mycobacterium tuberculosis

FURTHER INFORMATION

Joseph Heitman's laboratory

Cryptococcus neoformans cDNA Sequencing

Cryptococcus neoformans Genome Project

Cryptococcus neoformans Serotype A Database

Cryptococcus neoformans Serotype A Strain H99 Sequence

Cryptococcus neoformans Summary

The TIGR Cryptococcus neoformans Database

Glossary

MAT LOCUS

A mating-type locus is a region in a fungal genome that confers sexual identity.

GRANULOMA

A cluster of cells that is formed in response to specific infection agents.

HILAR LYMPH NODES

Specialized immune-system organs that are localized in the mediastinum (thoracic cavity) and that monitor infectious agents in the lung.

TRANSCYTOSIS

Movement of cells through other cells.

CONGENIC

Individuals that are identical at the genetic level, with the exception of one region. Often created by backcrossing during mating.

CLAMP CONNECTION

A short branch connecting one cell to the previous cell in hyphae, and a defining feature of the basidiomycetes.

PARASEXUAL

A form of reproduction characterized in fungi which enables mitotic recombination without meiosis, and usually involves reduction of a diploid to a haploid through whole-chromosome loss.

HOMEODOMAIN

A region of a protein that binds to DNA through a helix–turn–helix motif.

SYNAPTONEMAL COMPLEX

Protein structures that link homologous chromosomes to promote double strand breaks, causing recombination during meiosis.

ALVEOLUS

The smallest functional unit of the lung in which gas exchange occurs.

DIOECIOUS

A plant in which the male and female reproductive organs are located in flowers on different plants.

KELCH REPEAT

First discovered as repeated elements in the Drosophila Kelch ORF1 protein. A series of four to seven repeated kelch motifs is predicted to have a β-propeller-like tertiary structure, which mediates potential protein–protein interactions.

CALCINEURIN

A serine–threonine-specific protein phosphatase that is activated by calcium-calmodulin.

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Idnurm, A., Bahn, YS., Nielsen, K. et al. Deciphering the Model Pathogenic Fungus Cryptococcus Neoformans. Nat Rev Microbiol 3, 753–764 (2005). https://doi.org/10.1038/nrmicro1245

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