Cryptococcus neoformans: Difference between revisions
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__NOTOC__ | |||
{{Cryptococcosis}} | |||
{{Taxobox | {{Taxobox | ||
| | | image = Cryptococcus_neoformans2.jpg | ||
| width = 150px | |||
| image_caption = ''Cryptococcus neoformans'' | |||
| name = ''Cryptococcus neoformans'' | | name = ''Cryptococcus neoformans'' | ||
| regnum = | | regnum = Fungi | ||
| phylum = | | phylum = Basidiomycota | ||
| | | classis = Tremellomycetes | ||
| ordo = | | ordo = Tremellales | ||
| familia = | | familia = Tremellaceae | ||
| genus = | | genus = ''Cryptococcus'' | ||
| species = ''''' | | species = '''''Cryptococcus neoformans''''' | ||
}} | }} | ||
{{About0|Cryptococcosis}} | {{About0|Cryptococcosis}} | ||
{{CMG}} | {{CMG}} | ||
==Overview== | ==Overview== | ||
'''''Cryptococcus neoformans''''' is an encapsulated [[yeast]] that can live in both [[plant]]s and | '''''Cryptococcus neoformans''''' is an encapsulated [[yeast]] and an [[obligate aerobe]] that can live in both [[plant]]s and animals.<ref>{{Cite web|url=http://wwwnc.cdc.gov/eid/article/4/1/98-0109_article|title=What Makes Cryptococcus neoformans a Pathogen? - Volume 4, Number 1—March 1998 - Emerging Infectious Disease journal - CDC|website=wwwnc.cdc.gov|accessdate=2015-11-18}}</ref> <ref>{{Cite journal|last=Ingavale|first=Susham S.|last2=Chang|first2=Yun C.|last3=Lee|first3=Hyeseung|last4=McClelland|first4=Carol M.|last5=Leong|first5=Madeline L.|last6=Kwon-Chung|first6=Kyung J.|date=2008-09-01|title=Importance of Mitochondria in Survival of Cryptococcus neoformans Under Low Oxygen Conditions and Tolerance to Cobalt Chloride|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2528940/|journal=PLoS Pathogens|volume=4|issue=9|pages=e1000155|doi=10.1371/journal.ppat.1000155|issn=1553-7366|pmc=2528940|pmid=18802457}}</ref>It is often found in bird excrement. It is the causative agent of [[cryptococcosis]] (cryptococcal [[pneumonia]] and [[meningitis]]). | ||
== Classification == | == Classification == | ||
''Cryptococcus neoformans'' is composed of two | ''[[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 [[Contamination|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=1321–24 | 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 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> | ||
==Characteristics== | ==Characteristics== | ||
[[File:Cryptococcus1.jpg|thumb|left|''C. neoformans'' | [[File:Cryptococcus1.jpg|thumb|200px|left|''[[C. neoformans]]'' on [[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> | ''[[C. neoformans]]'' grows as a [[yeast]] ([[Unicellular organism|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 (anatomy)|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 stain|Gram-stained]] smears of [[purulent]] [[Exudate|exudates]] may be hampered by the presence of the large gelatinous [[Capsule (anatomy)|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 [[ | When grown as a [[yeast]], ''[[C. neoformans]]'' has a prominent [[Capsule (anatomy)|capsule]] composed mostly of [[polysaccharides]]. Under the microscope, the India ink [[stain]] is used for easy visualization of the [[capsule]] in [[cerebrospinal 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 (anatomy)|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 infection|Cryptococcal]] [[antigen]] from [[cerebrospinal fluid]] is thought to be the best test for diagnosis of [[Cryptococcal Meningitis|cryptococcal meningitis]] in terms of sensitivity, though it might be unreliable in [[Human Immunodeficiency Virus (HIV)|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 == | == 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 [[ | [[Image:Cryptococcosis of lung in patient with AIDS. Mucicarmine stain 962 lores.jpg|thumb|left|250px|''[[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 [[Infection|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. [[Infection|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 infection|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 /> | In human infection, ''[[C. neoformans]]'' is spread by [[inhalation]] of [[Aerosol|aerosolized]] basidiospores, and can [[Disseminated disease|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 [[Intracellular|intracellularly]] in [[macrophages]].<ref name="Fan" /> [[Intracellular]] survival appears to be the basis for latency, [[disseminated disease]], and [[Drug resistance|resistance]] to eradication by [[Antifungal agent|antifungal agents]]. One mechanism by which ''[[C. neoformans]]'' survives the hostile [[intracellular]] environment of the [[macrophage]] involves [[upregulation]] of [[Gene expression|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> | 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 [[Secretion|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> | ||
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 [[Diploid|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 [[Homolog|homologue]] of [[Gene|genes]] ''[[recA]]'' in [[bacteria]], and ''rad51'' in [[eukaryotes]] (see articles [[recA]] and rad51). ''Dmc1'' mediates [[homologous chromosome]] pairing during [[meiosis]] and repair of [[Double-stranded DNA helix|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]]. | |||
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 | |||
[[ | |||
== References == | == References == | ||
{{Reflist|2}} | {{Reflist|2}} | ||
[[Category: | [[Category:Fungal diseases]] | ||
Latest revision as of 17:30, 18 September 2017
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 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 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
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
- ↑ "What Makes Cryptococcus neoformans a Pathogen? - Volume 4, Number 1—March 1998 - Emerging Infectious Disease journal - CDC". wwwnc.cdc.gov. Retrieved 2015-11-18.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ [1]
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Tripathi K, Mor V, Bairwa NK, Del Poeta M, Mohanty BK. (2012)."Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice."
- ↑ 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
- ↑ Template:Cite doi
- ↑ 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.
- ↑ 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.
- ↑ 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
- ↑ 16.0 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
- ↑ 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
- ↑ Liu TB (2012). "Molecular mechanisms of cryptococcal meningitis". Virulence. 3 (2): 173–81. doi:10.4161/viru.18685. PMC 3396696. PMID 22460646.
- ↑ 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.
- ↑ http://medicalxpress.com/news/2014-06-fungal-protein-blood-brain-barrier.html
- ↑ 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
- ↑ 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