Cryptococcus neoformans

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Cryptococcus neoformans
Cryptococcus neoformans
Cryptococcus neoformans
Scientific classification
Kingdom: Fungi
Phylum: Basidiomycota
Class: Tremellomycetes
Order: Tremellales
Family: Tremellaceae
Genus: Cryptococcus
Species: Cryptococcus neoformans
This page is about microbiologic aspects of the organism(s).  For clinical aspects of the disease, see Cryptococcosis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Cryptococcus neoformans is an encapsulated yeast and an obligate aerobe that can live in both plants and animals.[1] [2]It is often found in bird excrement. It is the causative agent of cryptococcosis (cryptococcal pneumonia and meningitis).

Classification

Cryptococcus neoformans is composed of two varieties (v.): C. neoformans v. neoformans and C. n. v. grubii. A third variety, C. n. v. gattii, is now considered a distinct species, Cryptococcus gattii. C. n. v. grubii and C. n. v. neoformans have a worldwide distribution and are often found in soil contaminated by bird excrement. The genome sequence of C. neoformans v. neoformans was published in 2005.[3] Recent studies suggest colonies of C. neoformans and related fungi growing on the ruins of the melted down reactor of the chernobyl nuclear power plant may be able to use the energy of radiation (primary beta radiation) for "radiotrophic" growth.[4]

Characteristics

C. neoformans grows as a yeast (unicellular) and replicates by budding. It makes hyphae during mating, and eventually creates basidiospores at the end of the hyphae before producing spores. Under host-relevant conditions, including low glucose, serum, 5% carbon dioxide, and low iron, among others, the cells produce a characteristic polysaccharide capsule.[5] The recognition of C. neoformans in Gram-stained smears of purulent exudates may be hampered by the presence of the large gelatinous capsule which apparently prevents definitive staining of the yeast-like cells. In such stained preparations, it may appear either as round cells with Gram-positive granular inclusions impressed upon a pale lavender cytoplasmic background or as Gram-negative lipoid bodies.[6] When grown as a yeast, C. neoformans has a prominent capsule composed mostly of polysaccharides. Under the microscope, the India ink stain is used for easy visualization of the capsule in cerebrospinal fluid.[7] The particles of ink pigment do not enter the capsule that surrounds the spherical yeast cell, resulting in a zone of clearance or "halo" around the cells. This allows for quick and easy identification of C. neoformans. Unusual morphological forms are rarely seen.[8] For identification in tissue, mucicarmine stain provides specific staining of polysaccharide cell wall in C. neoformans. Cryptococcal antigen from cerebrospinal fluid is thought to be the best test for diagnosis of cryptococcal meningitis in terms of sensitivity, though it might be unreliable in HIV-positive patients.[9]

Pathology

C. neoformans seen in the lung of a patient with AIDS: The inner capsule of the organism stains red in this photomicrograph.

Infection with C. neoformans is termed cryptococcosis. Most infections with C. neoformans occur in the lungs.[10] However, fungal meningitis and encephalitis, especially as a secondary infection for AIDS patients, are often caused by C. neoformans, making it a particularly dangerous fungus. Infections with this fungus are rare in those with fully functioning immune systems.[11] So, C. neoformans is sometimes referred to as an opportunistic fungus.[11] It is a facultative intracellular pathogen.[12] Cryptococcus neoformans was the first intracellular pathogen for which the non-lytic escape process termed vomocytosis was observed.[13][14]

In human infection, C. neoformans is spread by inhalation of aerosolized basidiospores, and can disseminate to the central nervous system, where it can cause meningoencephalitis.[15] In the lungs, C. neoformans cells are phagocytosed by alveolar macrophages.[16] Macrophages produce oxidative and nitrosative agents, creating a hostile environment, to kill invading pathogens.[17] However, some C. neoformans cells can survive intracellularly in macrophages.[16] Intracellular survival appears to be the basis for latency, disseminated disease, and resistance to eradication by antifungal agents. One mechanism by which C. neoformans survives the hostile intracellular environment of the macrophage involves upregulation of expression of genes involved in responses to oxidative stress.[16]

Traversal of the blood–brain barrier by C. neoformans plays a key role in meningitis pathogenesis.[18] However, precise mechanisms by which it passes the blood-brain barrier are still unknown; one recent study in rats suggested an important role of secreted serine proteases.[19] The metalloprotease Mpr1 has been demonstrated to be critical in blood-brain barrier penetration.[20]

The vast majority of environmental and clinical isolates of C. neoformans are mating type a. Filaments of mating type a have haploid nuclei ordinarily, but these can undergo a process of diploidization (perhaps by endoduplication or stimulated nuclear fusion) to form diploid cells termed blastospores. The diploid nuclei of blastospores are able to undergo meiosis, including recombination, to form haploid basidiospores that can then be dispersed.[21] This process is referred to as monokaryotic fruiting. Required for this process is a gene designated dmc1, a conserved homologue of genes recA in bacteria, and rad51 in eukaryotes (see articles recA and rad51). Dmc1 mediates homologous chromosome pairing during meiosis and repair of double-strand breaks in DNA.[22] One benefit of meiosis in C. neoformans could be to promote DNA repair in the DNA-damaging environment caused by the oxidative and nitrosative agents produced in macrophages.[21] Thus, C. neoformans can undergo a meiotic process, monokaryotic fruiting, that may promote recombinational repair in the oxidative, DNA-damaging environment of the host macrophage, and this may contribute to its virulence.

References

  1. "What Makes Cryptococcus neoformans a Pathogen? - Volume 4, Number 1—March 1998 - Emerging Infectious Disease journal - CDC". wwwnc.cdc.gov. Retrieved 2015-11-18.
  2. Ingavale, Susham S.; Chang, Yun C.; Lee, Hyeseung; McClelland, Carol M.; Leong, Madeline L.; Kwon-Chung, Kyung J. (2008-09-01). "Importance of Mitochondria in Survival of Cryptococcus neoformans Under Low Oxygen Conditions and Tolerance to Cobalt Chloride". PLoS Pathogens. 4 (9): e1000155. doi:10.1371/journal.ppat.1000155. ISSN 1553-7366. PMC 2528940. PMID 18802457.
  3. Loftus BJ; et al. (2005). "The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans". Science. 307 (5713): 1321&ndash, 24. doi:10.1126/science.1103773. PMC 3520129. PMID 15653466.
  4. Dadachova E; et al. (2007). Rutherford, Julian, ed. "Ionizing Radiation Changes the Electronic Properties of Melanin and Enhances the Growth of Melanized Fungi". PLoS ONE. 2 (5): e457. doi:10.1371/journal.pone.0000457. PMC 1866175. PMID 17520016.
  5. [1]
  6. Bottone, E J. "Cryptococcus neoformans: pitfalls in diagnosis through evaluation of gram-stained smears of purulent exudates". National Center for Biotechnology Information. Journal of Clinical Microbiology. Retrieved 2014-11-19.
  7. Zerpa, R; Huicho, L; Guillén, A (September 1996). "Modified India ink preparation for Cryptococcus neoformans in cerebrospinal fluid specimens" (PDF). Journal of clinical microbiology. 34 (9): 2290–1. PMID 8862601.
  8. Shashikala; Kanungo, R; Srinivasan, S; Mathew, R; Kannan, M (Jul–Sep 2004). "Unusual morphological forms of Cryptococcus neoformans in cerebrospinal fluid". Indian journal of medical microbiology. 22 (3): 188–90. PMID 17642731.
  9. Antinori, Spinello; Radice, Anna; Galimberti, Laura; Magni, Carlo; Fasan, Marco; Parravicini, Carlo (November 2005). "The role of cryptococcal antigen assay in diagnosis and monitoring of cryptococcal meningitis". Journal of clinical microbiology. 43 (11): 5828–9. doi:10.1128/JCM.43.11.5828-5829.2005. PMC 1287839. PMID 16272534.
  10. Tripathi K, Mor V, Bairwa NK, Del Poeta M, Mohanty BK. (2012)."Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice."
  11. 11.0 11.1 What Makes Cryptococcus neoformans a Pathogen?, Kent L. Buchanan and Juneann W. Murphy University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  12. Template:Cite doi
  13. Alvarez, M; Casadevall, A (7 November 2006). "Phagosome extrusion and host-cell survival after Cryptococcus neoformans phagocytosis by macrophages". Current biology : CB. 16 (21): 2161–5. PMID 17084702.
  14. Ma, H; Croudace, JE; Lammas, DA; May, RC (7 November 2006). "Expulsion of live pathogenic yeast by macrophages". Current biology : CB. 16 (21): 2156–60. PMID 17084701.
  15. Velagapudi R, Hsueh YP, Geunes-Boyer S, Wright JR, Heitman J (2009). Spores as infectious propagules of Cryptococcus neoformans" Infect Immun 77(10) 4345-55. doi: 10.1128/IAI.00542-09. PMID 19620339
  16. 16.0 16.1 16.2 Fan W, Kraus PR, Boily MJ, Heitman J (2005). Cryptococcus neoformans gene expression during murine macrophage infection. Eukaryot Cell 4(8) 1420-1433. PMID 16087747
  17. Alspaugh JA, Granger DL (1991). Inhibition of Cryptococcus neoformans replication by nitrogen oxides supports the role of these molecules as effectors of macrophage-mediated cytostasis" Infect Immun 59(7) 2291-2296. PMID 2050398
  18. Liu TB (2012). "Molecular mechanisms of cryptococcal meningitis". Virulence. 3 (2): 173–81. doi:10.4161/viru.18685. PMC 3396696. PMID 22460646.
  19. Xu CY (Feb 2014). "permeability of blood-brain barrier is mediated by serine protease during Cryptococcus meningitis". J Int Med Res. 42 (1): 85–92. doi:10.1177/0300060513504365. PMID 24398759.
  20. http://medicalxpress.com/news/2014-06-fungal-protein-blood-brain-barrier.html
  21. 21.0 21.1 Lin X, Hull CM, Heitman J (2005). Sexual reproduction between partners of the same mating type in Cryptococcus neoformans" Nature 434(7036) 1017-1021. PMID 15846346
  22. Michod RE, Bernstein H, Nedelcu AM Adaptive value of sex in microbial pathogens" Infect Genet Evol 8(3) 267-285. Review. doi:10.1016/j.meegid.2008.01.002 PMID 18295550 http://www.hummingbirds.arizona.edu/Faculty/Michod/Downloads/IGE%20review%20sex.pdf

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