Cryptococcus neoformans

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cellular organisms - Eukaryota - Fungi/Metazoa group - Fungi - Dikarya - Basidiomycota - Agaricomycotina - Tremellomycetes - Tremellales - Tremellaceae - Filobasidiella - Filobasidiella/Cryptococcus neoformans species complex - Filobasidiella neoformans

Brief facts

• General description

  Cryptococcus neoformans (anamorph) or Filobasidiella neoformans (teleomorph) is an encapsulated heterobasidiomycetous fungus that usually grows as a yeast and replicates by budding. It is distributed worldwide and is often found in soil contaminated by avian feces.

• Disease

  F. neoformans is a causative agent of cryptococcosis, also known as Busse-Buschke disease, a disease that ranges from asymptomatic infection of airways to severe meningitis. The most common route of introduction of the infection is inhalation of fungal spores. The crucial factor of the disease outcome is believed to be not the pathogen's virulence but the immune status of the host. The emergence of the HIV virus promoted C. neoformans from a little-known pathogen to a common killer of immunocompromized patients. Cryptococcal meningoencephalitis is considered one of AIDS-defining conditions and is the third most frequent neurological complication in AIDS patients.

• Transmission

  Inhalation of airborne propagules from the environment is main pathway of infection. The major environmental sources are either soil contaminated with pigeon guano (C. neoformans var. neoformans and var. grubii) or eucalyptus trees and decaying wood (C. neoformans var. gattii - now C. bacillisporus). Cryptococcosis occurs in both animals and humans, but animal-to-animal or human-to-human transmission has not been documented, except for rare examples of iatrogenic (as a result of treatment) transmission. Other than being neurotropic, Cryptococcus can infect or spread to any organ to cause localized infections involving skin, eyes, myocardium, bones, joints, lungs, prostate gland, and urinary tract.

• Neurotropism

  There are three possible hypotheses that can explain the pathogen's predilection for the Central Nervous System (CNS):
  • specific neuronal substrates such as dopamine and epinephrine can facilitate fungal growth;
  • being a privileged tissue site in terms of vigorousness of immune responses, the CNS might provide safer environments for the fungus then other body sites;
  • specific receptors present on neuronal cells could be more attractive for Cryptococcus cells than other organs during systemic infection.

• The fungus has the following essential virulence factors:

  • Synthesis of the pigment melanin. Melanin protects the fungal cells against oxidative stress, phagocytosis, and antifungal drugs, and also can modify host immune responses.
  • Development of polysaccaride capsule, which helps the fungus cells to withstand phagocytosis by alveolar macrophages.
  • Ability to grow at body temperature (37-39°C). The vast majority of fungal species grow optimally between 25 and 35°C and there are only a few fungal species that appear thermotolerant and this physical characteristic is a pre-requisite phenotype for invasive mycoses in a mammalian host. Furthermore, C. neoformans cells can survive in the gastrointestinal tract of birds (~40°C), which in many instance responsible for environmental spread of the pathogen.

• Advantages of Cryptococcus neoformans as the model for studies of fungal pathogenesis:

  • A clinically important human pathogen. It has risen from a rare cause of human infection with less than 300 reported cases before 1955 to a common world-wide pathogen in the immunocompromized populations over the last decades. One study has found that the majotity of adult possess antibody to the fungus, and in New York city most children acquire antibodies to cryptococcal antigens before the age of 10.
  • A tractable genetic system, availability of various mutants.
  • Understanding of several virulence phenotypes.
  • Well-studied pathophysiology.
  • Robust animal models (rats, mice, and rabbits).

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Developmental stages

Life Cycle Stages

• parasexual parasexuality is a form of reproduction in fungi which enables mitotic recombination without meiosis, and usually involves reduction of a diploid to a haploid through whole-chromosome loss; in C. neoformans, in contrast to other fungi with parasexual cycles, meiosis occurs not only during mating but also during monokaryotic fruiting, resulting in recombinant haploid spores
  • monokaryotic
    fruiting the diploid hyphal cells are produced by fusion of haploid nuclei within single mating type; resulting filaments are mononucleate with unfused clamp connections (a short branches connecting one cell to the previous cell in hyphae), i. e. diploidization occurs early in filamentation before formation of the fruiting structures; monokaryotic fruiting predominates in mating type α
  • mating after fusion of cells from different mating types, the resulting hyphal cells contain two nuclei and are linked by fused clamp connections; the diploidization occurs from fusion of the nuclei inside of the fruiting structures
• asexual
  • vegetative growth
    • budding yeast a most common form of the fungus isolated from patients or from the environment
    • filamentous growth form of growth which preceeds sporulation; during this phase fusion of 1n nuclei within one mating type might occur and lead to monokaryotic fruiting

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Tissues

• basidium a terminal fruiting structures inside which the meiosis takes place; each basidium produces four tetrads of haploid spores
  • basidiospore haploid spores emerging from the basidium; it is hypothesized that the basidiospore, with its small size, might be the infectious propagule
• mycelium filamentous form of the fungus
• unicellular organism budding yeast form of the fungus

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Mating types

• mating type a less virulent mating type
• mating type α more virulent type; this type constitutes approximately 96% of all clinical isolates and in co-infections with both mating types is usually the one to enter the central nervous system; it is also a major type found in nature

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Appendix 1: MATα allele enhances filamentation

Lin X, Huang JC, Mitchell TG, Heitman J. Virulence attributes and hyphal growth of C. neoformans are quantitative traits and the MATalpha allele enhances filamentation. PLoS Genet. 2006 Nov 17;2(11):e187.

Fruiting in a and α Isolates Is Similar The filamentous isolate B3502a was cultured on V8 medium in the presence of synthetic α pheromone at 22 °C in the dark for two wk. The filamentous edge far from the original yeast growth patch was separated, fixed, and stained with DAPI. (A) The hyphae produced are monokaryotic with unfused clamps. (B) Four long chains of basidiospores were produced during fruiting. (C) Basidia with one, two, or four nuclei at different stages of basidium development were observed. In (A) and (C), the upper panel shows the DIC images, and the lower panel shows the corresponding fluorescent images. Scale bar, 10 μm.

Variation in Filamentous Growth during Fruiting A subset of the fruiting progeny derived from the cross between the nonfilamentous strain B3501α and the filamentous strain B3502a was examined microscopically. Cells were cultured on V8 medium for 25 d. Parental strains and several representative progeny displaying variations in hyphal growth are shown with the strain names listed below them.

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Appendix 2: cryptococcosis of the lung

Perfect JR. Management of cryptococcosis: how are we doing? PLoS Med. 2007 Feb;4(2):e47.

Cryptococcosis of the Lung in a Patient with AIDS Histopathology of lung shows widened alveolar septa containing a few inflammatory cells and numerous yeasts of the fungal pathogen C. neoformans. The inner layer of the yeast capsule stains red. Cryptococcosis is transmitted through inhalation of airborne yeast cells and/or biospores. At risk are the immunocompromised, especially those with HIV infection. Photo: CDC/Dr. Edwin P. Ewing, Jr.

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References

• Lin X, Heitman J. The biology of the Cryptococcus neoformans complex. Nat Rev Microbiol. 2005 Oct;3(10):753-64. PMID: 16704346
• Lin X et al. Virulence attributes and hyphal growth of C. neoformans are quantitative traits and the MATalpha allele enhances filamentation. PLoS Genet. 2006 Nov 17;2(11):e187. PMID: 17112316
• Idnurm A et al. Deciphering the model pathogenic fungus Cryptococcus neoformans. Nat Rev Microbiol. 2005 Oct;3(10):753-64. PMID: 16132036
• Perfect JR. Cryptococcus neoformans: a sugar-coated killer with designer genes. FEMS Immunol Med Microbiol. 2005 Sep 1;45(3):395-404. PMID: 16055314
• Perfect JR. Cryptococcus neoformans: the yeast that likes it hot. FEMS Yeast Res. 2006 Jun;6(4):463-8. PMID: 16696642

Websites

• Wikipedia: Cryptococcus neoformans
• eMedicine: Cryptococcosis

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