Editing Cryptococcus neoformans

{{Short description|Soil fungus that can cause disease}}
{{Speciesbox
| image = Cryptococcus neoformans using a light India ink staining preparation PHIL 3771 lores.jpg
| image_caption =Yeast state of ''Cryptococcus neoformans''
| genus = Cryptococcus (fungus)
| species = neoformans
| authority = (San Felice) [[Jean Paul Vuillemin|Vuill.]] (1901)
| synonyms = ''Saccharomyces neoformans'' <small>San Felice (1895)</small><br />
''Filobasidiella neoformans'' <small>Kwon-Chung (1975)</small>
}}

'''''Cryptococcus neoformans''''' is an [[bacterial capsule|encapsulated]] [[basidiomycetous]] [[yeast]]<ref name=Buchanan>{{Cite journal|title = What makes ''Cryptococcus neoformans'' a pathogen?| journal = Emerging Infectious Diseases|volume = 4|issue = 1|pages = 71–83|doi = 10.3201/eid0401.980109|pmid = 9452400|pmc = 2627665|year = 1998|last1 = Buchanan|first1 = Kent|last2 = Murphy|first2 = J. W.}}</ref> belonging to the class [[Tremellomycetes]] and an [[obligate aerobe]]<ref>{{Cite journal|title = Importance of mitochondria in survival of ''Cryptococcus neoformans'' under low oxygen conditions and tolerance to Cobalt Chloride|journal = PLOS Pathogens|date = 2008-09-01|issn = 1553-7366|pmc = 2528940|pmid = 18802457|volume = 4|issue = 9|doi = 10.1371/journal.ppat.1000155| first1 = Susham S.|last1 = Ingavale|first2 = Yun C.|last2 = Chang|first3 = Hyeseung|last3 = Lee|first4 = Carol M.|last4 = McClelland|first5 = Madeline L.|last5 = Leong|first6 = Kgung J.|last6 = Kwon-Chung|pages=e1000155 | doi-access=free }}</ref> that can live in both plants and animals. Its [[teleomorph]] is a filamentous [[fungus]], formerly referred to ''Filobasidiella neoformans''. In its yeast state, it is often found in [[bird]] excrement. It has remarkable genomic plasticity and genetic variability between its strains, making treatment of the disease it causes difficult.<ref name=":0" /> ''Cryptococcus neoformans'' [[cryptococcosis|causes disease]] primarily in [[immunocompromised]] hosts, such as HIV or cancer patients.<ref name=Buchanan/><ref>{{Cite journal|last1=Bahn|first1=Yong-Sun|last2=Sun|first2=Sheng|last3=Heitman|first3=Joseph|last4=Lin|first4=Xiaorong|date=2020-09-01|title=Microbe Profile: Cryptococcus neoformans species complex|journal=Microbiology|language=en|volume=166|issue=9|pages=797–799|doi=10.1099/mic.0.000973|doi-access=free |issn=1350-0872|pmc=7717486|pmid=32956032}}</ref><ref name=":1" /> In addition it has been shown to cause disease in apparently immunocompetent hosts, especially in developed countries.

==Classification==
''Cryptococcus neoformans'' has undergone numerous nomenclature revisions since its first description in 1895. It formerly contained two [[varieties (biology)|varieties]]: ''C. neoformans ''var.'' neoformans'' and ''C. neoformans '' var.'' grubii''. A third variety, ''C. neoformans ''var.'' gattii'', was later defined as a distinct species, ''[[Cryptococcus gattii]]''. The most recent classification system divides these varieties into seven species.<ref>{{Cite journal|last1=Hagen|first1=Ferry|last2=Khayhan|first2=Kantarawee|last3=Theelen|first3=Bart|last4=Kolecka|first4=Anna|last5=Polacheck|first5=Itzhack|last6=Sionov|first6=Edward|last7=Falk|first7=Rama|last8=Parnmen|first8= Sittiporn|last9=Lumbsch|first9=H. Thorsten|date=2015-05-01|title=Recognition of seven species in the ''Cryptococcus gattii/Cryptococcus neoformans'' species complex|journal=Fungal Genetics and Biology|volume=78|pages=16–48|doi= 10.1016/j.fgb.2015.02.009|issn=1096-0937|pmid=25721988|doi-access=free}}</ref> ''C. neoformans'' refers to ''C. neoformans '' var.'' grubii''. A new species name, ''Cryptococcus deneoformans'', is used for the former ''C. neoformans ''var.'' neoformans''. ''C. gattii'' is divided into five species.{{citation needed|date=January 2023}}

The teleomorph was first described in 1975 by K.J. Kwon-Chung, who obtained cultures of ''Filobasidiella neoformans'' by crossing strains of the yeast ''C. neoformans''. She was able to observe [[basidia]] similar to those of the genus ''[[Filobasidium]]'', hence the name ''Filobasidiella'' for the new genus.<ref>{{cite journal |doi=10.2307/3758842 |author=Kwon-Chung KJ. |year=1975 |title=A new genus, ''Filobasidiella'', the perfect state of ''Cryptococcus neoformans'' |jstor=3758842 |journal=Mycologia |volume=67 |issue= 6|pages=1197–1200 |pmid=765816}}</ref> Following changes to the [[International Code of Nomenclature for algae, fungi, and plants]], the practice of giving different names to teleomorph and [[anamorph]] forms of the same fungus was discontinued, meaning that ''Filobasidiella neoformans'' became a synonym of the earlier name ''Cryptococcus neoformans''.{{citation needed|date=January 2023}}

==Characteristics==
[[File:Cryptococcus Gram film.jpg|thumb|left|''C. neoformans'' stained by [[Gram stain]]]]
{{technical|section|date=February 2020}}
''Cryptococcus neoformans'' typically grows as a [[yeast]] (unicellular) and replicates by [[budding]]. It makes [[hypha]]e 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">{{cite book |editor1-last=Heitman |editor1-first=Joseph |editor2-last=Kozel |editor2-first=Thomas R. |editor3-last=Kwon-Chung |editor3-first=Kyung J. |editor4-last=Perfect |editor4-first=John R. |editor5-last=Casadevall |editor5-first=Arturo |title=Cryptococcus: From Human Pathogen to Model Yeast |date=2011 |location=Washington, DC |isbn=9781683671220|doi= 10.1128/9781555816858|publisher=ASM Press}}</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 journal|last1=Bottone|first1=E J|title=Cryptococcus neoformans: pitfalls in diagnosis through evaluation of gram-stained smears of purulent exudates|journal=Journal of Clinical Microbiology|pmc=273699|pmid =6171578| volume=12|issue=6|year=1980|pages=790–1|doi=10.1128/jcm.12.6.790-791.1980}}</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|doi=10.1128/JCM.34.9.2290-2291.1996|pmid=8862601|pmc=229234}}</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|doi=10.1016/S0255-0857(21)02835-8|pmid=17642731|doi-access=free}}</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|url= https://air.unimi.it/bitstream/2434/6221/2/Antinori.pdf}}</ref>

The first genome sequence for a strain of ''C. neoformans'' (var. ''neoformans''; now ''C. deneoformans'') was published in 2005.<ref name=":1">{{cite journal |author=Coussement |first1=Julien |last2=Heath |first2=Christopher |last3=Roberts |first3=Matthew |last4=Lane |first4=Rebekah |last5=Spelman |first5=Tim |last6=Smibert |first6=Olivia |last7=Longhitano |first7=Anthony |last8=Morrisey |first8=Orla |last9=Nield |first9=Blake |last10=Tripathy |first10=Monica |last11=Davis |first11=Joshua |last12=Kennedy |first12=Karina |last13=Lynar |first13=Sarah |last14=Crawford |first14=Lucy |last15=Slavin |first15=Monica |display-authors= |date=26 May 2023 |title=Current Epidemiology and Clinical Features of Cryptococcus Infection in Patients Without Human Immunodeficiency Virus: A Multicenter Study in 46 Hospitals in Australia and New Zealand |url=https://academic.oup.com/cid/article/77/7/976/7180396 |journal=Clinical Infectious Diseases |volume=77 |issue=7 |pages=976–986 |doi=10.1093/cid/ciad321|pmid=37235212 }}</ref>

Studies suggest that colonies of ''C. neoformans'' and related fungi growing within the ruins of the [[Chernobyl Nuclear Power Plant]] may be able to metabolize [[ionizing radiation]].<ref>{{cite journal|year=2007|title=Ionizing Radiation Changes the Electronic Properties of Melanin and Enhances the Growth of Melanized Fungi|journal=PLOS ONE|volume=2|issue=5|pages= e457|doi=10.1371/journal.pone.0000457|pmc=1866175|pmid=17520016|author=Dadachova E|editor1-last=Rutherford|editor1-first=Julian|display-authors=etal|bibcode=2007PLoSO...2..457D|doi-access=free}}</ref>

==Pathology==
Infection with ''C. neoformans'' is termed [[cryptococcosis]]. Most infections with ''C. neoformans'' occur in the lungs, as the fungus enters its host through the respiratory route.<ref>{{cite journal | last1 = Tripathi | first1 = K | last2 = Mor | first2 = V | last3 = Bairwa | first3 = NK |author4-link=Maurizio Del Poeta| last4 = Del Poeta | first4 = M | last5 = Mohanty | first5 = BK | year = 2012 | title = Hydroxyurea treatment inhibits proliferation of Cryptococcus neoformans in mice | journal = Front Microbiol| volume = 3| pages = 187| pmid = 22783238 | doi=10.3389/fmicb.2012.00187 | pmc=3390589| doi-access = free }}</ref> Because it is normally a harmless soil fungus, ''C. neoformans'' must first adapt to its new environment inside the human body, making several [[Virulence|virulent]] transformations, including the formation of a [[polysaccharide]] [[Bacterial capsule|capsule]]. The specific factors that enable this transformation involve sensory receptor proteins common to most soil fungi (pH sensors, carbon dioxide sensors, and intracellular iron detectors) which have been adapted to induce ''C. neoformans'' cells into rapidly becoming a dangerous, disease-causing organism.<ref>{{Cite journal |last=Alspaugh |first=J. Andrew |date=May 2015 |title="Virulence Mechanisms and Cryptococcus neoformans pathogenesis" |journal=Fungal Genetics and Biology |volume=78 |pages=55–58 |doi=10.1016/j.fgb.2014.09.004 |issn=1087-1845 |pmc=4370805 |pmid=25256589}}</ref>

The fungus is a [[facultative intracellular pathogen]]<ref>{{Cite journal | last1 = Alvarez | first1 = M. | last2 = Burns | first2 = T. | last3 = Luo | first3 = Y. | last4 = Pirofski | first4 = L. A. |author-link4=Liise-anne Pirofski | last5 = Casadevall | first5 = A. | title = The outcome of Cryptococcus neoformans intracellular pathogenesis in human monocytes | journal = BMC Microbiology | volume = 9 | pages = 51 | year = 2009 | pmid = 19265539 | pmc = 2670303 | doi = 10.1186/1471-2180-9-51 | doi-access = free }}</ref> that can utilize host [[phagocytes]] to spread within the body.<ref>{{cite journal|last1=Charlier|first1=C|last2=Nielsen|first2=K|last3=Daou|first3=S|last4=Brigitte|first4=M|last5=Chretien|first5=F| last6=Dromer|first6=F|title=Evidence of a role for monocytes in dissemination and brain invasion by Cryptococcus neoformans.|journal=Infection and Immunity|date=January 2009|volume=77|issue=1|pages=120–7|pmid=18936186|doi= 10.1128/iai.01065-08|pmc=2612285|citeseerx=10.1.1.336.3329}}</ref><ref>{{cite journal|last1=Sabiiti|first1=W|last2=Robertson|first2=E|last3=Beale|first3=MA|last4=Johnston|first4=SA|last5=Brouwer|first5=AE|last6=Loyse|first6=A|last7 =Jarvis|first7=JN|last8=Gilbert|first8=AS|last9=Fisher|first9=MC|last10=Harrison|first10=TS|last11=May|first11=RC|last12=Bicanic|first12=T|title=Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis.|journal=The Journal of Clinical Investigation|date=May 2014|volume=124|issue=5|pages=2000–8|pmid=24743149|doi=10.1172/jci72950|pmc=4001551}}</ref> ''C. 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|date=7 November 2006|volume=16|issue=21|pages=2161–5|pmid=17084702|doi=10.1016/j.cub.2006.09.061|s2cid=1612240|doi-access=free|bibcode=2006CBio...16.2161A}}</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|date=7 November 2006|volume=16|issue=21|pages=2156–60|pmid=17084701|doi=10.1016/j.cub.2006.09.032|s2cid= 11639313|doi-access=free|bibcode=2006CBio...16.2156M}}</ref> It has been speculated that this ability to manipulate host cells results from environmental selective pressure by amoebae, a hypothesis first proposed by [[Arturo Casadevall]] under the term "accidental virulence".<ref>{{cite book|last1=Casadevall|first1=A|chapter=Amoeba Provide Insight into the Origin of Virulence in Pathogenic Fungi|title=Recent Advances on Model Hosts|date=2012|volume=710|pages=1–10|pmid=22127880|doi= 10.1007/978-1-4419-5638-5_1|series=Advances in Experimental Medicine and Biology|isbn=978-1-4419-5637-8}}</ref>

In human infection, ''C. neoformans'' is spread by inhalation of aerosolized basidiospores or dehydrated fungal cells, and can disseminate to the central nervous system, where it can cause meningoencephalitis.<ref>{{cite journal |vauthors=Velagapudi R, Hsueh YP, Geunes-Boyer S, Wright JR, Heitman J | year = 2009 | title = Spores as infectious propagules of ''Cryptococcus neoformans'' | journal = Infect Immun | volume = 77 | issue = 10| pages = 4345–55 | doi = 10.1128/IAI.00542-09 | pmid = 19620339 | pmc=2747963}}</ref> In the lungs, ''C. neoformans'' cells are phagocytosed by alveolar macrophages.<ref name=Fan>{{cite journal |vauthors=Fan W, Kraus PR, Boily MJ, Heitman J | year = 2005 | title = ''Cryptococcus neoformans'' gene expression during murine macrophage infection | journal = Eukaryot Cell | volume = 4 | issue = 8| pages = 1420–1433 | doi = 10.1128/EC.4.8.1420-1433.2005 | pmid = 16087747 | pmc=1214536| citeseerx = 10.1.1.333.7376}}</ref> Macrophages produce oxidative and nitrosative agents, creating a hostile environment, to kill invading pathogens.<ref>{{cite journal |vauthors=Alspaugh JA, Granger DL | year = 1991 | title = Inhibition of Cryptococcus neoformans replication by nitrogen oxides supports the role of these molecules as effectors of macrophage-mediated cytostasis | journal = Infect Immun | volume = 59 | issue = 7| pages = 2291–2296 | pmid = 2050398 | pmc=258009 | doi = 10.1128/IAI.59.7.2291-2296.1991}}</ref> However, some ''C. neoformans'' cells can survive intracellularly in macrophages because of the protective nature of the polysaccharide capsule as well as its ability to produce melanin.<ref name="Fan"/><ref name=":0" /> Intracellular survival appears to be one of the factors contributing to latency, disseminated disease, and [[Antimicrobial resistance|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; a 2014 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 | pages = 85–92 | doi=10.1177/0300060513504365| doi-access = free }}</ref>  The [[metalloprotease]] Mpr1 has been demonstrated to be critical in blood-brain barrier penetration.<ref>{{Cite web | url=http://medicalxpress.com/news/2014-06-fungal-protein-blood-brain-barrier.html | title=Fungal protein found to cross blood-brain barrier|date=12 June 2014|publisher=[[University of California at Davis]]|via=MedicalXpress}}</ref>

=== AIDS ===
[[Fungal meningitis]] and [[encephalitis]] are frequently associated with [[HIV/AIDS|HIV]]-positive patients with low [[T cell|T-cell]] counts. ''C. neoformans'' is one of the illnesses that definitionally marks the point at which a person with HIV may be considered to have [[AIDS-defining clinical condition|AIDS]].<ref>{{Cite web |date=2008-12-05 |title=Appendix A: AIDS-Defining Conditions |url=https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2.htm |archive-url=https://web.archive.org/web/20250101034823/https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5710a2.htm |archive-date=2025-01-01 |access-date=2025-02-05 |website=cdc.gov}}</ref> Infections with this fungus were thought to be rare in people with fully functioning immune systems, hence ''C. neoformans'' is often referred to as an opportunistic pathogen.<ref name="Buchanan" /> However, a study from 2024 done in Australia and New Zealand showed the vast majority of recorded infections to be in non-HIV patients.<ref name=":1" />

=== Changes in reproductive pattern ===
The vast majority of environmental and clinical isolates of ''C. neoformans'' are mating type alpha. Filaments of mating type alpha have haploid nuclei ordinarily, but these can undergo a process of diploidization (perhaps by endoduplication or stimulated nuclear fusion) to form diploid cells termed [[blastospore]]s. The diploid nuclei of blastospores are able to undergo meiosis, including recombination, to form haploid basidiospores that can then be dispersed.<ref name=Lin>{{cite journal |vauthors=Lin X, Hull CM, Heitman J | year = 2005 | title = Sexual reproduction between partners of the same mating type in ''Cryptococcus neoformans'' | journal = Nature | volume = 434 | issue = 7036| pages = 1017–1021 | pmid = 15846346 | doi=10.1038/nature03448| bibcode = 2005Natur.434.1017L | s2cid = 52857557 }}</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>{{cite journal |vauthors=Michod RE, Bernstein H, Nedelcu AM | title = Adaptive value of sex in microbial pathogens | journal = Infect Genet Evol | volume = 8 | issue = 3| pages = 267–285 | doi = 10.1016/j.meegid.2008.01.002 | pmid=18295550 | date=May 2008| bibcode = 2008InfGE...8..267M }}</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.{{citation needed|date=January 2023}}

==Serious complications of human infection==
Infection begins in the lungs, and from there the fungus can disseminate to the brain and other body parts via macrophages. An infection of the brain caused by ''C. neoformans'' is referred to as cryptococcal meningitis, which is most often fatal when left untreated.<ref name=":1" /><ref>{{cite journal |last1=Bicanic |first1=Tihana |last2=Harrison |first2=Thomas S. |date=1 January 2004 |title=Cryptococcal meningitis |journal=British Medical Bulletin |volume=72 |issue=1 |pages=99–118 |doi=10.1093/bmb/ldh043 |issn=1471-8391 |pmid=15838017}}</ref> Cryptococcal meningitis causes more than 180,000 deaths annually.<ref name="chen">{{cite journal |last1=Chen |first1=Lei |last2=Tian |first2=Xiuyun |last3=Zhang |first3=Lanyue |last4=Wang |first4=Wenzhao |last5=Hu |first5=Pengjie |last6=Ma |first6=Zhongyi |last7=Li |first7=Yeqi |last8=Li |first8=Shibin |last9=Shen |first9=Zhenghao |last10=Fan |first10=Xin |last11=Ye |first11=Leixin |last12=Ke |first12=Weixin |last13=Wu |first13=Yao |last14=Shui |first14=Guanghou |last15=Xiao |first15=Meng |display-authors=5 |date=15 January 2024 |title=Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis |journal=Nature Microbiology |volume=9 |issue=2 |pages=346–358 |doi=10.1038/s41564-023-01561-1 |issn=2058-5276 |pmid=38225460 |last16=He |first16=Guang-jun |last17=Yang |first17=Ying |last18=Fang |first18=Wenxia |last19=Bai |first19=Fan |last20=Liao |first20=Guojian |last21=Chen |first21=Min |last22=Lin |first22=Xiaorong |last23=Li |first23=Chong |last24=Wang |first24=Linqi}}</ref> CNS (central nervous system) infections may also be present as a brain abscesses known as ''cryptococcomas'', subdural effusions, dementia, isolated cranial nerve lesions, spinal cord lesions, and ischemic stroke. The estimated one-year mortality of HIV-related people who receive treatment for cryptococcal meningitis is 70% in low-income countries versus 20–30% for high-income countries.<ref name=rajasingham>{{cite journal |display-authors=5| last1=Rajasingham | first1=Radha | last2=Smith | first2=Rachel M | last3=Park | first3=Benjamin J | last4=Jarvis | first4=Joseph N | last5=Govender | first5=Nelesh P | last6=Chiller | first6=Tom M | last7=Denning | first7=David W | last8=Loyse | first8=Angela | last9=Boulware | first9=David R | title=Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis | journal=The Lancet Infectious Diseases | volume=17 | issue=8 | date=2017 | pmid=28483415 | pmc=5818156 | doi=10.1016/S1473-3099(17)30243-8| pages=873–881}}</ref> Symptoms include headache, fever, neck stiffness, nausea and vomiting, photophobia. Diagnosis methods include a serum cryptococcal antigen test and lumbar puncture with cerebrospinal fluid (CSF) examination to detect ''C. neoformans''.<ref>{{cite book| title=Guidelines for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV | publisher=World Health Organization (WHO)| date=27 June 2022| url=https://www.who.int/publications/i/item/9789240052178|isbn=978-92-4-005217-8}}</ref>

==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. Mucicarmine stain is used in this case, staining the inner capsule of the organism red.]]
Cryptococcosis that does not affect the central nervous system can be treated with [[fluconazole]] alone.

It was recommended in 2000 that cryptococcal meningitis be treated for two weeks with intravenous [[amphotericin B]] 0.7–1.0&nbsp;mg/kg per day and oral [[flucytosine]] 100&nbsp;mg/kg per day (or [[intravenous]] flucytosine 75&nbsp;mg/kg per day{{Citation needed|date=November 2024}}day if the patient is unable to swallow), followed by oral fluconazole 400–800&nbsp;mg daily for ten weeks<ref name=":0">{{cite journal |last1=Melhem |first1=Marcia |last2=Júnior |first2=Diniz |last3=Takahashi |first3=Juliana |last4=Macioni |first4=Milena |last5=Oliveira |first5=Lidiane |last6=Siufi de Araújo |first6=Lisandra |last7=Fava |first7=Wellington |last8=Bonfietti |first8=Lucas |last9=Paniago |first9=Anamaria |last10=Venturini |first10=James |last11=Espinel-Ingroff |first11=Ana |display-authors= |date=29 January 2024 |title=Antifungal Resistance in Cryptococcal Infections |journal=Pathogens |volume=13 |issue=2 |pages=128 |doi=10.3390/pathogens13020128 |doi-access=free |pmid=38392866 |pmc=10891860 }}</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=2615–26 |vauthors=Martínez E, García-Viejo MA, Marcos MA |pmid=11101078 | doi=10.1097/00002030-200011100-00029 |display-authors=etal| doi-access=free }}</ref><ref name=":2">{{cite journal |last1=Diehl |first1=Camila |last2=Pinzan |first2=Camila |last3=Alves de Castro |first3=Patrícia |last4=Delbaje |first4=Endrews |last5=García Carnero |first5=Laura |last6=Sánchez-León |first6=Eddy |last7=Bhalla |first7=Kabir |last8=Kronstad |first8=James |last9=Kim |first9=Dong-gyu |last10=Doering |first10=Tamara |last11=Alkhazraji |first11=Sondus |last12=Misha |first12=Nagendra |last13=Idrahin |first13=Ashraf |last14=Yoshimura |first14=Mami |last15=Goldman |first15=Gustavo |display-authors= |date=25 June 2024 |title=Brilacidin, a novel antifungal agent against Cryptococcus neoformans |journal=mBio |volume=15 |issue=2 |pages=e01031-24 |doi=10.1128/mbio.01031-24 |pmid=38916308 |pmc=11253610 }}</ref>  [[Flucytosine]] is a generic, off-patent medicine, but the cost of two weeks of flucytosine therapy is about [[US$]]10,000,{{Citation needed|date=November 2024|reason=Also, when?}} so that flucytosine has been unavailable in low- and middle-income countries. In 1970, flucytosine was available in Africa.<ref>{{cite journal |vauthors=Mpairwe Y, Patel KM | year = 1970 | title = Cryptococcal meningitis in Mulago Hospital, Kampala | journal = East Afr Med J. | volume = 47 | issue = 8| pages = 445–7 | pmid = 5479794 }}</ref>  A dose of 200&nbsp;mg/kg per day of flucytosine is associated with more side effects but is not more effective.{{Citation needed|date=November 2024}}

A single high dose of liposomal amphotericin B with 14 days of flucytosine and fluconazole is recommended by the newest WHO guideline for cryptococcal meningitis.<ref>{{cite web | url=https://www.who.int/news/item/20-04-2022-rapid-advice-new-guidelines-for-simpler-safer-treatment-for-cryptococcal-disease-in-plhiv | title=New guidelines from WHO recommend a simpler, safer treatment for cryptococcal disease in people living with HIV }}</ref> A new study found that brain glucose can trigger amphotericin B (AmB) tolerance of ''C. neoformans'' during meningitis which means it needs longer treatment time to kill the fungal cells. The study found that the brain glucose induced AmB tolerance of ''C. neoformans'' via glucose repression activator Mig1. Mig1 inhibits the production of ergosterol, the target of AmB, and promotes the production of inositol phosphoryl ceramide (IPC), which competes with AmB for ergosterol to limit AmB efficacy in mouse brain and human CSF. Strikingly, Results of this study indicated that IPC synthase inhibitor aureobasidin A (AbA) can enhance the anti-cryptococcal activity of AmB. AbA+AmB AmB had an even better therapeutic effect in a mouse model of cryptococcal meningitis than AmB+flucytosine which may bring new hope for the treatment of Cryptococcal meningitis.<ref name=chen/>

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 |author1=CF Schaars |author2=Meintjes GA |author3=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|hdl=11427/14193 |doi-access=free }}</ref> but prospective studies from [[Uganda]] and Malawi reported that higher doses of 1200&nbsp;mg per day have more fungicidal activity.<ref>{{cite journal |vauthors=Longley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, Wall E, Andia I, Jaffar S, Harrison TS | year = 2008 | title = Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda | journal = Clin Infect Dis | volume = 47 | issue = 12| pages = 1556–61 | doi = 10.1086/593194 | pmid=18990067| doi-access = free }}</ref> The outcomes with fluconazole monotherapy have 30% worse survival than amphotericin-based therapies, in a recent systematic review.<ref>{{cite journal |vauthors=Rajasingham R, Rolfes MA, Birkenkamp KE, Meya DB, Boulware DR | year = 2012 | title = Cryptococcal meningitis treatment strategies in resource-limited settings: a cost-effectiveness analysis | journal = PLOS Med | volume = 9 | issue = 9| page = e1001316 | doi = 10.1371/journal.pmed.1001316 | pmid = 23055838 | pmc=3463510 | doi-access = free }}</ref>

The current treatment options for cryptococcosis are not optimal for treatment.<ref name=":0" /> AmB is highly toxic to humans, and both fluconazole and flucytosine have been shown to cause development of drug resistanse in ''C. neoformans''. A recent study from 2024 suggested brilacidin as an alternative treatment option.<ref name=":2" /> Brilacidin was shown to be non-toxic and it caused no drug resistance development in ''C. neoformans'', while still being efficient at causing fungal mortality. Brilacidin enhances permiability of the cell wall and membrane by binding to ergosterol and disrupting its distribution. It also affects the cell wall integrity pathway and disrupts calsium metabolism. Through these methods it not only causes cell mortality on its own, but also enables more effective use of other antifungal agents such as AmB against ''C. neoformans.''

==References==
{{Reflist|24em}}

==External links==
* {{Commons category-inline|Cryptococcus neoformans}}
* [http://www.scq.ubc.ca/?p=525 A good overview of ''Cryptococcus neoformans'' biology from the Science Creative Quarterly]
* [https://web.archive.org/web/20180425032214/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]

{{Mycoses}}
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