Editing Cryptococcus neoformans (section)

==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}}