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==Overview==
==Overview==
'''''Cryptococcus neoformans''''' is an encapsulated yeast-like [[fungus]] that can live in both [[plant]]s and [[animal]]s.This species, also known by its [[teleomorph]] name, ''Filobasidiella neoformans'', belongs to the broad class of organisms called "club fungi" or [[Basidiomycota|Division Basidiomycota]], which is one the five major types of fungi.  ''C. neoformans'' usually grows as a [[yeast]] (unicellular) and replicates by [[budding]].  Under certain conditions, both in nature and in the laboratory, ''C. neoformans'' can grow as a filamentous fungus as pictured here: [http://tolweb.org/tree/ToLimages/Filobasidiella_neoformans.jpg picture of the organism]<ref>[[Photomicrograph]] hosted by the [http://tolweb.org/tree/phylogeny.html Tree of Life project] and specifically contributed by the [http://www.dumru.mc.duke.edu/ Duke University Mycology Research Unit]; the picture is part of the [http://tolweb.org/tree?group=Hymenomycetes&contgroup=Basidiomycota Hymenomycetes article].  Retrieved 2005-03-15</ref>.  When grown as a yeast, ''C. neoformans'' has a prominent capsule composed mostly of [[polysaccharides]].  Microscopically, the [[India ink]] stain is used for easy visualization of the capsule.  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.
'''''Cryptococcus neoformans''''' is an encapsulated [[yeast]] that can live in both [[plant]]s and [[animal]]s. Its [[teleomorph]] is ''Filobasidiella neoformans'', a filamentous [[fungus]] belonging to the [[class (biology)|class]] [[Tremellomycetes]]. It is often found in [[bird]] excrement.
[[Image:Cryptococcosis of lung in patient with AIDS. Mucicarmine stain 962 lores.jpg|thumb|right|250px|'''Cryptococcus neoformans''' seen in the lung of a patient with AIDS. The inner capsule of the organism stains red in this photomicrograph]]
The species ''C. neoformans'' is composed of three variants (v.): ''C. neoformans v. gattii'', ''v. grubii'', and ''v. neoformans''.  ''C. neoformans v. gattii'' is found mostly in the [[tropics]], but has also been confirmed on southern [[Vancouver Island]] on the southwestern [[coast]] of [[Canada]]. ''Cryptococcus gattii'' has recently been shown to be different enough from other subspecies to be elevated to its own species level. ''C. neoformans v. grubii'' and ''v. neoformans'' have a worldwide distribution and are often found in soil which has been contaminated by bird excrement.  The genome sequence of ''C. neoformans v. neoformans'' was published in 2005.<ref>{{cite journal | author=Loftus BJ, et al. | title=The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans | journal=Science | volume=307 | issue=5713 | pages=1321&ndash;24 | id=PMID 15653466 }}</ref> Recent studies made on [[Chernobyl Nuclear Power Plant]] have shown that colonies of ''Cryptococcus neoformans'' developed on the ruins of [[nuclear meltdown|melted down]] reactor harvest energy of [[particle radiation|radiation]] (primary [[beta radiation]] from [[caesium-137]]) itself.<ref>{{cite journal | author=Dadachova E, ''et al.'' | title=Ionizing Radiation Changes the Electronic Properties of Melanin and Enhances the Growth of Melanized Fungi | journal=PLoS One | volume=2(5)| doi=10.1371/journal.pone.0000457 | id=PMID 17520016 }}</ref> 


Infection with ''C. neoformans'' is termed [[cryptococcosis]].
== Classification ==
''Cryptococcus neoformans'' is composed of two [[varieties (biology)|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.<ref>{{cite journal | author=Loftus BJ | title=The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans | journal=Science | volume=307 | issue=5713 | pages=1321&ndash;24 | pmid=15653466 | doi=10.1126/science.1103773 | year=2005 | pmc=3520129|display-authors=etal}}</ref> Recent studies suggest colonies of ''C. neoformans'' and related fungi growing on the ruins of the [[nuclear meltdown|melted down]] reactor of the [[Chernobyl nuclear power plant]] may be able to use the energy of [[particle radiation|radiation]] (primary [[beta radiation]]) for "[[Radiotrophic fungus|radiotrophic]]" growth.<ref>{{cite journal | author=Dadachova E | title=Ionizing Radiation Changes the Electronic Properties of Melanin and Enhances the Growth of Melanized Fungi | journal=PLoS ONE | volume=2| doi=10.1371/journal.pone.0000457 | pmid=17520016  | year=2007 | pages=e457 | issue=5 | pmc=1866175 | editor1-last=Rutherford | editor1-first=Julian|display-authors=etal}}</ref>


==Treatment==
==Characteristics==
[[File:Cryptococcus Gram film.jpg|thumb|left|''C. neoformans'' stained by [[Gram stain]]]]
''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.<ref name="Cryptococcus: From Human Pathogen to Model Yeast, Editors: Joseph Heitman, Thomas R. Kozel, Kyung J. Kwon-Chung, John R Perfect, and Arturo Casadevall">[http://estore.asm.org/viewItemDetails.asp?ItemID=920]</ref> 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.<ref name="JCM Article">{{cite web|last1=Bottone|first1=E J|title=Cryptococcus neoformans: pitfalls in diagnosis through evaluation of gram-stained smears of purulent exudates.|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC273699/|website=National Center for Biotechnology Information|publisher=Journal of Clinical Microbiology|accessdate=2014-11-19}}</ref>
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 cerebral spinal fluid.<ref name="pmid8862601">{{cite journal|last=Zerpa|first=R|author2=Huicho, L |author3=Guillén, A |title=Modified India ink preparation for Cryptococcus neoformans in cerebrospinal fluid specimens.|journal=Journal of clinical microbiology|date=September 1996|volume=34|issue=9|pages=2290–1|pmid=8862601|url=http://jcm.asm.org/content/34/9/2290.full.pdf}}</ref> 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.<ref name="pmid17642731">{{cite journal|last=Shashikala|author2=Kanungo, R |author3=Srinivasan, S |author4=Mathew, R |author5= Kannan, M |title=Unusual morphological forms of Cryptococcus neoformans in cerebrospinal fluid.|journal=Indian journal of medical microbiology|date=Jul–Sep 2004|volume=22|issue=3|pages=188–90|pmid=17642731|url=http://www.ijmm.org/article.asp?issn=0255-0857;year=2004;volume=22;issue=3;spage=188;epage=190;aulast=Shashikala}}</ref> 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.<ref name="pmid16272534">{{cite journal|last=Antinori|first=Spinello|author2=Radice, Anna |author3=Galimberti, Laura |author4=Magni, Carlo |author5=Fasan, Marco |author6= Parravicini, Carlo |title=The role of cryptococcal antigen assay in diagnosis and monitoring of cryptococcal meningitis.|journal=Journal of clinical microbiology|date=November 2005|volume=43|issue=11|pages=5828–9|pmid=16272534|pmc=1287839|doi=10.1128/JCM.43.11.5828-5829.2005}}</ref>
 
== Pathology ==
Infection with ''C. neoformans'' is termed [[cryptococcosis]]. Most infections with ''C. neoformans'' occur in the lungs.<ref>Tripathi K, Mor V, Bairwa NK, Del Poeta M, Mohanty BK. (2012).[http://www.ncbi.nlm.nih.gov/pubmed/22783238 "Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice."]</ref> 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.<ref name="cdcpathogen">[http://www.cdc.gov/ncidod/eid/vol4no1/buchanan.htm What Makes Cryptococcus neoformans a Pathogen?], Kent L. Buchanan and Juneann W. Murphy University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA</ref> So, ''C. neoformans'' is sometimes referred to as an opportunistic fungus.<ref name="cdcpathogen" /> It is a [[facultative intracellular pathogen]].<ref>{{cite doi|10.1186/1471-2180-9-51}}</ref>  ''Cryptococcus neoformans'' was the first intracellular pathogen for which the non-lytic escape process termed [[vomocytosis]] was observed.<ref>{{cite journal|last1=Alvarez|first1=M|last2=Casadevall|first2=A|title=Phagosome extrusion and host-cell survival after Cryptococcus neoformans phagocytosis by macrophages.|journal=Current biology : CB|date=7 November 2006|volume=16|issue=21|pages=2161–5|pmid=17084702}}</ref><ref>{{cite journal|last1=Ma|first1=H|last2=Croudace|first2=JE|last3=Lammas|first3=DA|last4=May|first4=RC|title=Expulsion of live pathogenic yeast by macrophages.|journal=Current biology : CB|date=7 November 2006|volume=16|issue=21|pages=2156–60|pmid=17084701}}</ref>
 
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.<ref>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</ref> In the lungs, ''C. neoformans'' cells are phagocytosed by alveolar macrophages.<ref name=Fan>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</ref> Macrophages produce oxidative and nitrosative agents, creating a hostile environment, to kill invading pathogens.<ref>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</ref> However, some ''C. neoformans'' cells  can survive intracellularly in macrophages.<ref name="Fan"/> 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.<ref name=Fan />
 
Traversal of the blood–brain barrier by ''C. neoformans'' plays a key role in meningitis pathogenesis.<ref name=" pmid = 22460646 ">{{cite journal | author = Liu TB | title = Molecular mechanisms of cryptococcal meningitis. | journal = Virulence |pmid = 22460646 | doi=10.4161/viru.18685 | pmc=3396696 | volume=3 | issue=2 | year=2012 | pages=173–81}}</ref> 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.<ref name=" pmid = 24398759 ">{{cite journal | author = Xu CY | title = permeability of blood-brain barrier is mediated by serine protease during Cryptococcus meningitis. | journal = J Int Med Res | volume = 42 | issue = 1|date=Feb 2014 | pmid = 24398759 | url = http://imr.sagepub.com/content/42/1/85.full  | pages = 85–92 | doi=10.1177/0300060513504365}}</ref>  The [[metalloprotease]] Mpr1 has been demonstrated to be critical in blood-brain barrier penetration.<ref>http://medicalxpress.com/news/2014-06-fungal-protein-blood-brain-barrier.html</ref>
 
'''Meiosis (sexual reproduction), another possible survival factor for intracellular ''C. neoformans'''''
 
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.<ref name=Lin>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</ref> 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.<ref>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</ref> 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.<ref name=Lin />  Thus, ''C. neoformans'' can undergo a [[Meiosis|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.
 
== Treatment ==
[[Image:Cryptococcosis of lung in patient with AIDS. Mucicarmine stain 962 lores.jpg|thumb|right|250px|''C. neoformans'' seen in the lung of a patient with AIDS: The inner capsule of the organism stains red in this photomicrograph.]]
Cryptococcosis that does not affect the central nervous system can be treated with [[fluconazole]] alone.
Cryptococcosis that does not affect the central nervous system can be treated with [[fluconazole]] alone.


Cryptococcal meningitis should be treated for two weeks with [[intravenous]] [[Amphotericin B]] 0.7&ndash;1.0 (mg/kg)/day and oral [[flucytosine]] 100 (mg/kg)/day (or [[intravenous]] flucytosine 75 (mg/kg)/day if the patient is unable to swallow).  This should then be followed by oral fluconazole 200mg daily for ten weeks<ref>{{cite journal | author=Saag MS, Graybill RJ, Larsen RA, ''et al.'' | title=Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. |journal=Clin Infect Dis | year=2000 | volume=30 | issue=4 | pages=710&ndash;8 | id=PMID 10770733 }}</ref> and then 200 mg daily until the patient's [[CD4]] count is above 100 for three months and his HIV [[viral load]] is undetectable.<ref>{{cite journal | title=Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy
Cryptococcal meningitis should be treated for two weeks with [[intrathecally|intrathecal]] [[amphotericin B]] 0.7&ndash;1.0&nbsp;mg/kg/day and oral [[flucytosine]] 100&nbsp;mg/kg/day (or [[intravenous]] flucytosine 75&nbsp;mg/kg/day if the patient is unable to swallow).  This should then be followed by oral fluconazole 400–800&nbsp;mg daily for ten weeks<ref>{{cite journal | author=Saag MS, Graybill RJ, Larsen RA | title=Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America |journal=Clin Infect Dis | year=2000 | volume=30 | issue=4 | pages=710&ndash;8 | pmid=10770733 | doi=10.1086/313757 |display-authors=etal}}</ref> and then 200&nbsp;mg daily for at least one year and until the patient's [[CD4]] count is above 200 cells/mcl.<ref>{{cite journal | title=Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy
  | journal=AIDS | volume=14 | issue=16 | year=2000 | pages=2615&ndash;26 | author=Martínez E, García-Viejo MA, Marcos MA, ''et al.''|id=PMID 11101078 }}</ref><ref>{{cite journal | title=Discontinuation of secondary prophylaxis for Cryptococcal meningitis in Human Immunodeficiency Virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study | author=Vibhagool A, Sungkanuparph S, Mootsikapun P, ''et al.'' | journal=Clin Infect Dis | volume=36 | year=2003 | pages=1329&ndash;31 |
  | journal=AIDS | volume=14 | issue=16 | year=2000 | pages=2615&ndash;26 | author=Martínez E, García-Viejo MA, Marcos MA|pmid=11101078 | doi=10.1097/00002030-200011100-00029 |display-authors=etal}}</ref><ref>{{cite journal | title=Discontinuation of secondary prophylaxis for Cryptococcal meningitis in Human Immunodeficiency Virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study | author=Vibhagool A, Sungkanuparph S, Mootsikapun P | journal=Clin Infect Dis | volume=36 | year=2003 | pages=1329&ndash;31 |
doi=10.1086/374849 | id=PMID 12746781 }}</ref>
doi=10.1086/374849 | pmid=12746781 | issue=10 |display-authors=etal}}</ref>  [[Flucytosine]] is a generic, off-patent medicine. However, a market failure exists, with a two-week cost of flucytosine therapy being about $10,000. As a result, flucytosine is currently universally unavailable in low- and middle-income countries.  In 1970, flucytosine was available in Africa.<ref>Mpairwe Y, Patel KM.  Cryptococcal meningitis in Mulago Hospital, Kampala. ''East Afr Med J. ''1970;47:445-7. PMID 5479794</ref>


Intravenous [[Ambisome]] 4 (mg/kg)/day may be used but is not superior: its main use is in patients who do not tolerate Amphotericin B.  The 200 (mg/kg)/day dose for flucytosine is not more effective, is associated with more side-effects and should not be used.
Intravenous [[ambisome]] 4 (mg/kg)/day may be used but is not superior; its main use is in patients who do not tolerate amphotericin B.  The dose of 200&nbsp;mg/kg/day for flucytosine is not more effective, is associated with more side effects and should not be used.


In Africa, oral fluconazole at a rate of 200 mg daily is used. However, this does not result in cure because it merely suppresses the fungus and does not kill it; viable fungus can continue to be grown from [[cerebrospinal fluid|CSF]] of patients who have taken fluconazole for many months.  An increased dose of 400 mg daily does not improve outcomes,<ref>{{cite journal | title=Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole | author=CF Schaars, Meintjes GA, Morroni C, ''et al.'' | journal=BMC Infect Dis | year=2006 | volume=6 | pages=118 | doi=10.1186/1471-2334-6-118 }}</ref> but preliminary data from [[Uganda]] shows that very high doses of 1200 mg or more per day may be effective. The duration of this treatment and the post-treatment maintenance dose is not known.
In Africa, oral fluconazole at a rate of 200&nbsp;mg daily is often used. However, this does not result in cure, because it merely suppresses the fungus and does not kill it; viable fungus can continue to be grown from [[cerebrospinal fluid]] of patients not having taken fluconazole for many months.  An increased dose of 400&nbsp;mg daily does not improve outcomes,<ref>{{cite journal | title=Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole | author=CF Schaars, Meintjes GA, Morroni C | journal=BMC Infect Dis | year=2006 | volume=6 | pages=118 | doi=10.1186/1471-2334-6-118 | pmid=16846523 | pmc=1540428 |display-authors=etal}}</ref> but prospective studies from [[Uganda]] and Malawi reported that higher doses of 1200&nbsp;mg per day have more fungicidal activity.<ref>Longley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, Wall E, Andia I, Jaffar S, Harrison TS. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. ''Clin Infect Dis''. 2008;47:1556-61. [[doi: 10.1086/593194]].</ref> The outcomes with fluconazole monotherapy have 30% worse survival than amphotericin-based therapies, in a recent systematic review.<ref>Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR. Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis" ''PLoS Med'' 2012; 9: e1001316. .{{doi| 10.1371/journal.pmed.1001316}} PMID 23055838</ref>


== References ==
{{Reflist|2}}


==References==
== External links ==
{{Reflist|2}}
{{Commons category|Cryptococcus neoformans}}
* [http://www.scq.ubc.ca/?p=525 A good overview of ''Cryptococcus neoformans'' biology from the Science Creative Quarterly]
* [http://www.metapathogen.com/cryptococcus/ ''Cryptococcus neoformans'' biology, general information, life cycle image at MetaPathogen]
* [http://www.biomedcentral.com/1471-2180/9/51 The outcome of ''Cryptococcus neoformans'' intracellular pathogenesis in human monocytes]


==External links==
{{Mycoses}}
*[http://www.scq.ubc.ca/?p=525 A good overview of Cryptococcus neoformans biology from the Science Creative Quarterly]


[[de:Cryptococcus neoformans]]
[[Category:Infectious Disease Project]]
[[fr:Cryptococcus neoformans]]
[[Category:Yeasts]]

Revision as of 18:42, 5 August 2015

Cryptococcus neoformans
Scientific classification
Kingdom: Fungi
Phylum: Basidiomycota
Subphylum: Basidiomycotina
Order: Sporidiales
Family: Sporidiobolaceae
Genus: Filobasidiella (Cryptococcus)
Species: Filobasidiella neoformans
(Cryptococcus neoformans)

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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 that can live in both plants and animals. Its teleomorph is Filobasidiella neoformans, a filamentous fungus belonging to the class Tremellomycetes. It is often found in bird excrement.

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.[1] 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.[2]

Characteristics

File:Cryptococcus Gram film.jpg
C. neoformans stained by Gram stain

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.[3] 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.[4] 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 cerebral spinal fluid.[5] 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.[6] 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.[7]

Pathology

Infection with C. neoformans is termed cryptococcosis. Most infections with C. neoformans occur in the lungs.[8] 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.[9] So, C. neoformans is sometimes referred to as an opportunistic fungus.[9] It is a facultative intracellular pathogen.[10] Cryptococcus neoformans was the first intracellular pathogen for which the non-lytic escape process termed vomocytosis was observed.[11][12]

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.[13] In the lungs, C. neoformans cells are phagocytosed by alveolar macrophages.[14] Macrophages produce oxidative and nitrosative agents, creating a hostile environment, to kill invading pathogens.[15] However, some C. neoformans cells can survive intracellularly in macrophages.[14] 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.[14]

Traversal of the blood–brain barrier by C. neoformans plays a key role in meningitis pathogenesis.[16] 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.[17] The metalloprotease Mpr1 has been demonstrated to be critical in blood-brain barrier penetration.[18]

Meiosis (sexual reproduction), another possible survival factor for intracellular C. neoformans

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.[19] 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.[20] 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.[19] 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.

Treatment

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

Cryptococcosis that does not affect the central nervous system can be treated with fluconazole alone.

Cryptococcal meningitis should be treated for two weeks with intrathecal amphotericin B 0.7–1.0 mg/kg/day and oral flucytosine 100 mg/kg/day (or intravenous flucytosine 75 mg/kg/day if the patient is unable to swallow). This should then be followed by oral fluconazole 400–800 mg daily for ten weeks[21] and then 200 mg daily for at least one year and until the patient's CD4 count is above 200 cells/mcl.[22][23] Flucytosine is a generic, off-patent medicine. However, a market failure exists, with a two-week cost of flucytosine therapy being about $10,000. As a result, flucytosine is currently universally unavailable in low- and middle-income countries. In 1970, flucytosine was available in Africa.[24]

Intravenous ambisome 4 (mg/kg)/day may be used but is not superior; its main use is in patients who do not tolerate amphotericin B. The dose of 200 mg/kg/day for flucytosine is not more effective, is associated with more side effects and should not be used.

In Africa, oral fluconazole at a rate of 200 mg daily is often used. However, this does not result in cure, because it merely suppresses the fungus and does not kill it; viable fungus can continue to be grown from cerebrospinal fluid of patients not having taken fluconazole for many months. An increased dose of 400 mg daily does not improve outcomes,[25] but prospective studies from Uganda and Malawi reported that higher doses of 1200 mg per day have more fungicidal activity.[26] The outcomes with fluconazole monotherapy have 30% worse survival than amphotericin-based therapies, in a recent systematic review.[27]

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ [1]
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ Tripathi K, Mor V, Bairwa NK, Del Poeta M, Mohanty BK. (2012)."Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice."
  9. ↑ 9.0 9.1 What Makes Cryptococcus neoformans a Pathogen?, Kent L. Buchanan and Juneann W. Murphy University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  10. ↑ Template:Cite doi
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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
  14. ↑ 14.0 14.1 14.2 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
  15. ↑ 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
  16. ↑ Liu TB (2012). "Molecular mechanisms of cryptococcal meningitis". Virulence. 3 (2): 173–81. doi:10.4161/viru.18685. PMC 3396696. PMID 22460646.
  17. ↑ 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.
  18. ↑ http://medicalxpress.com/news/2014-06-fungal-protein-blood-brain-barrier.html
  19. ↑ 19.0 19.1 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
  20. ↑ 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
  21. ↑ Saag MS, Graybill RJ, Larsen RA; et al. (2000). "Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America". Clin Infect Dis. 30 (4): 710&ndash, 8. doi:10.1086/313757. PMID 10770733.
  22. ↑ Martínez E, García-Viejo MA, Marcos MA; et al. (2000). "Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy". AIDS. 14 (16): 2615&ndash, 26. doi:10.1097/00002030-200011100-00029. PMID 11101078.
  23. ↑ Vibhagool A, Sungkanuparph S, Mootsikapun P; et al. (2003). "Discontinuation of secondary prophylaxis for Cryptococcal meningitis in Human Immunodeficiency Virus-infected patients treated with highly active antiretroviral therapy: a prospective, multicenter, randomized study". Clin Infect Dis. 36 (10): 1329&ndash, 31. doi:10.1086/374849. PMID 12746781.
  24. ↑ Mpairwe Y, Patel KM. Cryptococcal meningitis in Mulago Hospital, Kampala. East Afr Med J. 1970;47:445-7. PMID 5479794
  25. ↑ CF Schaars, Meintjes GA, Morroni C; et al. (2006). "Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole". BMC Infect Dis. 6: 118. doi:10.1186/1471-2334-6-118. PMC 1540428. PMID 16846523.
  26. ↑ Longley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, Wall E, Andia I, Jaffar S, Harrison TS. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin Infect Dis. 2008;47:1556-61. doi: 10.1086/593194.
  27. ↑ Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR. Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis" PLoS Med 2012; 9: e1001316. .doi: 10.1371/journal.pmed.1001316 PMID 23055838

External links

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