Editing Candida albicans (section)

==Morphology==
''C. albicans'' exhibits a wide range of [[morphology (biology)|morphologica]]l [[phenotype]]s due to phenotypic switching and bud to hypha transition. The yeast-to-hyphae transition (filamentation) is a rapid process and induced by environmental factors. Phenotypic switching is spontaneous, happens at lower rates and in certain strains up to seven different phenotypes are known. The best studied switching mechanism is the white to opaque switching (an epigenetic process). Other systems have been described as well. Two systems (the high-frequency switching system and white to opaque switching) were discover by [[David R. Soll]] and colleagues.<ref name="auto">{{cite journal | vauthors = Slutsky B, Staebell M, Anderson J, Risen L, Pfaller M, Soll DR | title = "White-opaque transition": a second high-frequency switching system in Candida albicans | journal = Journal of Bacteriology | volume = 169 | issue = 1 | pages = 189–197 | date = January 1987 | pmid = 3539914 | pmc = 211752 | doi = 10.1128/jb.169.1.189-197.1987 }}</ref><ref name="High-frequency switching of colony">{{cite journal | vauthors = Slutsky B, Buffo J, Soll DR | title = High-frequency switching of colony morphology in Candida albicans | journal = Science | volume = 230 | issue = 4726 | pages = 666–669 | date = November 1985 | pmid = 3901258 | doi = 10.1126/science.3901258 | bibcode = 1985Sci...230..666S }}</ref> Switching in ''C. albicans'' is often, but not always, influenced by environmental conditions such as the level of CO<sub>2</sub>, anaerobic conditions, medium used and temperature.<ref name="High-frequency switching in Candida">{{cite journal | vauthors = Soll DR | title = High-frequency switching in Candida albicans | journal = Clinical Microbiology Reviews | volume = 5 | issue = 2 | pages = 183–203 | date = April 1992 | pmid = 1576587 | pmc = 358234 | doi = 10.1128/cmr.5.2.183 }}</ref>
In its yeast form ''C. albicans'' ranges from 10 to 12 [[Micrometre|microns]].<ref>{{cite book |vauthors=Reiss E, DiSalvo A |veditors=Hunt RC |title=Microbiology and Immunology On-line |date=2018 |url=https://www.microbiologybook.org/mycology/2018mycology-3.htm |access-date=7 September 2020 |chapter=Mycology - Yeasts |archive-date=3 January 2021 |archive-url=https://web.archive.org/web/20210103011954/http://www.microbiologybook.org/mycology/2018mycology-3.htm |url-status=live }}</ref> Spores can form on the pseudohyphae called [[chlamydospore]]s which survive when put in unfavorable conditions such as dry or hot seasons.<ref name="microbewiki.kenyon.edu">{{cite web | url = https://microbewiki.kenyon.edu/index.php/Candida_albicans | vauthors = Foss S | date = 22 July 2013 | title = Candida albicans | access-date = 24 October 2017 | archive-date = 18 November 2023 | archive-url = https://web.archive.org/web/20231118161321/https://microbewiki.kenyon.edu/index.php/Candida_albicans | url-status = live }}</ref>
[[File:Candida albicans mixed colony.jpg|thumb|An opaque colony of ''C. albicans'' growing as yeast-like cells with filamentous ''C. albicans'' cells on top]]

===Yeast-to-hypha switching===

Although often referred to as '''dimorphic''', ''C. albicans'' is, in fact, [[polyphenism|polyphenic]] (often also referred to as [[pleomorphism (microbiology)|pleomorphic]]).<ref>{{cite journal | vauthors = Staniszewska M, Bondaryk M, Siennicka K, Kurzatkowski W | title = Ultrastructure of Candida albicans pleomorphic forms: phase-contrast microscopy, scanning and transmission electron microscopy | journal = Polish Journal of Microbiology | volume = 61 | issue = 2 | pages = 129–135 | year = 2012 | pmid = 23163212 | doi = 10.33073/pjm-2012-016 | doi-access = free }}</ref> When cultured in standard yeast laboratory medium, ''C. albicans'' grows as ovoid "yeast" cells. However, mild environmental changes in temperature, CO<sub>2</sub>, nutrients and pH can result in a morphological shift to filamentous growth.<ref>{{cite journal | vauthors = Si H, Hernday AD, Hirakawa MP, Johnson AD, Bennett RJ | title = Candida albicans white and opaque cells undergo distinct programs of filamentous growth | journal = PLOS Pathogens | volume = 9 | issue = 3 | pages = e1003210 | date = March 2013 | pmid = 23505370 | pmc = 3591317 | doi = 10.1371/journal.ppat.1003210 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sudbery PE | title = Growth of Candida albicans hyphae | journal = Nature Reviews. Microbiology | volume = 9 | issue = 10 | pages = 737–748 | date = August 2011 | pmid = 21844880 | doi = 10.1038/nrmicro2636 | s2cid = 205498076 }} See [https://www.nature.com/articles/nrmicro2636#figure-title figure 2] {{Webarchive|url=https://web.archive.org/web/20181215142754/https://www.nature.com/articles/nrmicro2636#figure-title |date=2018-12-15 }}.</ref> Filamentous cells share many similarities with yeast cells. Both cell types seem to play a specific, distinctive role in the survival and pathogenicity of ''C. albicans''. Yeast cells seem to be better suited for the dissemination in the bloodstream while hyphal cells have been proposed as a virulence factor. Hyphal cells are invasive and speculated to be important for tissue penetration, colonization of organs and surviving plus escaping macrophages.<ref>{{cite journal | vauthors = Sudbery P, Gow N, Berman J | title = The distinct morphogenic states of Candida albicans | journal = Trends in Microbiology | volume = 12 | issue = 7 | pages = 317–324 | date = July 2004 | pmid = 15223059 | doi = 10.1016/j.tim.2004.05.008 }}</ref><ref>{{cite journal | vauthors = Jiménez-López C, Lorenz MC | title = Fungal immune evasion in a model host-pathogen interaction: Candida albicans versus macrophages | journal = PLOS Pathogens | volume = 9 | issue = 11 | pages = e1003741 | year = 2013 | pmid = 24278014 | pmc = 3836912 | doi = 10.1371/journal.ppat.1003741 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Berman J, Sudbery PE | title = Candida Albicans: a molecular revolution built on lessons from budding yeast | journal = Nature Reviews. Genetics | volume = 3 | issue = 12 | pages = 918–930 | date = December 2002 | pmid = 12459722 | doi = 10.1038/nrg948 | s2cid = 29341377 }}</ref> The transition from yeast to hyphal cells is termed to be one of the key factors in the virulence of ''C. albicans''; however, it is not deemed necessary.<ref>{{cite journal | vauthors = Shareck J, Belhumeur P | title = Modulation of morphogenesis in Candida albicans by various small molecules | journal = Eukaryotic Cell | volume = 10 | issue = 8 | pages = 1004–1012 | date = August 2011 | pmid = 21642508 | pmc = 3165445 | doi = 10.1128/EC.05030-11 }}</ref> When ''C. albicans'' cells are grown in a medium that mimics the physiological environment of a human host, they grow as filamentous cells (both true hyphae and pseudohyphae). ''C. albicans'' can also form [[chlamydospore]]s, the function of which remains unknown, but it is speculated they play a role in surviving harsh environments as they are most often formed under unfavorable conditions.<ref name="Staib2007">{{cite journal | vauthors = Staib P, Morschhäuser J | title = Chlamydospore formation in Candida albicans and Candida dubliniensis--an enigmatic developmental programme | journal = Mycoses | volume = 50 | issue = 1 | pages = 1–12 | date = January 2007 | pmid = 17302741 | doi = 10.1111/j.1439-0507.2006.01308.x | s2cid = 7387908 }}</ref>

The cAMP-PKA signaling cascade is crucial for the morphogenesis and an important transcriptional regulator for the switch from yeast like cells to filamentous cells is EFG1.<ref>{{cite journal | vauthors = Sohn K, Urban C, Brunner H, Rupp S | title = EFG1 is a major regulator of cell wall dynamics in Candida albicans as revealed by DNA microarrays | journal = Molecular Microbiology | volume = 47 | issue = 1 | pages = 89–102 | date = January 2003 | pmid = 12492856 | doi = 10.1046/j.1365-2958.2003.03300.x | s2cid = 23743789 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Shapiro RS, Robbins N, Cowen LE | title = Regulatory circuitry governing fungal development, drug resistance, and disease | journal = Microbiology and Molecular Biology Reviews | volume = 75 | issue = 2 | pages = 213–267 | date = June 2011 | pmid = 21646428 | pmc = 3122626 | doi = 10.1128/MMBR.00045-10 }}</ref>
[[File:Whiteopaquecandida.jpg|Round, white-phase and elongated, opaque-phase ''Candida albicans'' cells: the scale bar is 5 μm|thumb]]
[[File:Whiteopaqueregulation.jpg|thumb|In this model of the genetic network regulating the white-opaque switch, the white and gold boxes represent genes enriched in the white and opaque states, respectively. The blue lines represent relationships based on genetic epistasis. Red lines represent Wor1 control of each gene, based on Wor1 enrichment in chromatin immunoprecipitation experiments. Activation (arrowhead) and repression (bar) are inferred based on white- and opaque-state expression of each gene.]]

===High-frequency switching===

Besides the well-studied yeast-to-hyphae transition other switching systems have been described.<ref>{{cite journal | vauthors = Soll DR | title = The role of phenotypic switching in the basic biology and pathogenesis of Candida albicans | journal = Journal of Oral Microbiology | volume = 6 | issue = 2 | pages = 895–9 | date = January 2014 | pmid = 24455104 | pmc = 3895265 | doi = 10.3402/jom.v6.22993 }}</ref> One such system is the "high-frequency switching" system. During this switching different cellular morphologies ([[phenotype]]s) are generated spontaneously. This type of switching does not occur en masse, represents a variability system and it happens independently from environmental conditions.<ref name="High-frequency switching in Candida"/> The strain 3153A produces at least seven different colony morphologies.<ref>{{cite journal | vauthors = Alby K, J R | title = To switch or not to switch?: Phenotypic switching is sensitive to multiple inputs in a pathogenic fungus | journal = Communicative & Integrative Biology | volume = 2 | issue = 6 | pages = 509–511 | date = November 2009 | pmid = 20195457 | pmc = 2829826 | doi = 10.4161/cib.2.6.9487 }}</ref><ref name="High-frequency switching of colony"/><ref>{{cite journal | vauthors = Vargas K, Wertz PW, Drake D, Morrow B, Soll DR | title = Differences in adhesion of Candida albicans 3153A cells exhibiting switch phenotypes to buccal epithelium and stratum corneum | journal = Infection and Immunity | volume = 62 | issue = 4 | pages = 1328–1335 | date = April 1994 | pmid = 8132340 | pmc = 186281 | doi = 10.1128/IAI.62.4.1328-1335.1994 }}</ref> In many strains the different phases convert spontaneously to the other(s) at a low frequency. The switching is reversible, and colony type can be inherited from one generation to another.
Being able to switch through so many different (morphological) phenotypes makes ''C. albicans'' able to grow in different environments, both as a commensal and as a pathogen.<ref name="ReferenceC"/>

In the 3153A strain, a gene called [[Sirtuin 2|''SIR2'']] (for silent information regulator), which seems to be important for phenotypic switching, has been found.<ref>{{cite journal | vauthors = Pérez-Martín J, Uría JA, Johnson AD | title = Phenotypic switching in Candida albicans is controlled by a SIR2 gene | journal = The EMBO Journal | volume = 18 | issue = 9 | pages = 2580–2592 | date = May 1999 | pmid = 10228170 | pmc = 1171338 | doi = 10.1093/emboj/18.9.2580 }}</ref><ref>{{cite book | vauthors = Dean L, McEntyre J | chapter = How Candida albicans switches phenotype - and back again | date = 24 November 1999 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK2316/ | title = Coffee Break: Tutorials for NCBI Tools | publisher = National Center for Biotechnology Information (US) | language = en | access-date = 7 January 2020 | archive-date = 8 July 2022 | archive-url = https://web.archive.org/web/20220708140134/https://www.ncbi.nlm.nih.gov/books/NBK2316/ | url-status = live }}</ref> ''SIR2'' was originally found in ''[[Saccharomyces cerevisiae]]'' (brewer's yeast), where it is involved in [[Gene silencing|chromosomal silencing]]—a form of [[transcriptional regulation]], in which regions of the [[genome]] are reversibly inactivated by changes in [[chromatin]] structure (chromatin is the complex of [[DNA]] and proteins that make [[chromosome]]s). In yeast, genes involved in the control of mating type are found in these silent regions, and ''SIR2'' represses their expression by maintaining a silent-competent chromatin structure in this region.<ref>{{cite web|url=https://www.yeastgenome.org/locus/S000002200|title=SIR2 {{pipe}} SGD|website=www.yeastgenome.org|access-date=2020-01-07|archive-date=2023-11-18|archive-url=https://web.archive.org/web/20231118161523/https://www.yeastgenome.org/locus/S000002200|url-status=live}}</ref> The discovery of a ''C. albicans SIR2'' implicated in phenotypic switching suggests it, too, has silent regions controlled by ''SIR2'', in which the phenotype-specific genes may reside. How ''SIR2'' itself is regulated in ''S. cerevisiae'' may yet provide more clues as to the switching mechanisms of ''C. albicans''.{{citation needed|date=August 2022}}

===White-opaque switching===

Next to the [[sexual dimorphism|dimorphism]] and the first described high-frequency switching system ''C. albicans'' undergoes another high-frequency switching process called white-opaque switching, which is another [[phenotypic switching]] process in ''C. albicans''. It was the second high-frequency switching system discovered in ''C. albicans''.<ref name="auto"/> The white-opaque switch is an [[Epigenetics|epigenetic]] switching system.<ref name="ReferenceA">{{cite journal | vauthors = Rikkerink EH, Magee BB, Magee PT | title = Opaque-white phenotype transition: a programmed morphological transition in Candida albicans | journal = Journal of Bacteriology | volume = 170 | issue = 2 | pages = 895–899 | date = February 1988 | pmid = 2828333 | pmc = 210739 | doi = 10.1128/jb.170.2.895-899.1988 }}</ref> Phenotypic switching is often used to refer to white-opaque switching, which consists of two phases: one that grows as round cells in smooth, white colonies (referred to as white form) and one that is rod-like and grows as flat, gray colonies (called opaque form). This switch between white cells and opaque cells is important for the virulence and the [[mating of yeast|mating]] process of ''C. albicans'' as the opaque form is the [[mating in fungi|mating]] competent form, being a million times more efficient in mating compared to the white type.<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Lohse MB, Johnson AD | title = White-opaque switching in Candida albicans | journal = Current Opinion in Microbiology | volume = 12 | issue = 6 | pages = 650–654 | date = December 2009 | pmid = 19853498 | pmc = 2812476 | doi = 10.1016/j.mib.2009.09.010 }}</ref><ref>{{cite book |vauthors=Hnisz D, Tscherner M, Kuchler K |title=Yeast Genetic Networks |chapter=Morphological and Molecular Genetic Analysis of Epigenetic Switching of the Human Fungal Pathogen Candida albicans |volume=734 |issue=2 |pages=303–315 |year=2011 |doi=10.1007/978-1-61779-086-7_15|pmid=21468996|series=Methods in Molecular Biology |isbn=978-1-61779-085-0}}</ref> This switching between white and opaque form is regulated by the WOR1 regulator (White to Opaque Regulator 1) which is controlled by the [[mating type]] locus (MTL) repressor (a1-α2) that inhibits the expression of WOR1.<ref>{{cite journal | vauthors = Morschhäuser J | title = Regulation of white-opaque switching in Candida albicans | journal = Medical Microbiology and Immunology | volume = 199 | issue = 3 | pages = 165–172 | date = August 2010 | pmid = 20390300 | doi = 10.1007/s00430-010-0147-0 | s2cid = 8770123 }}</ref> Besides the white and opaque phase there is also a third one: the gray phenotype. This phenotype shows the highest ability to cause cutaneous infections. The white, opaque, and gray phenotypes form a phenotypic switching system where white cells switch to and from the opaque phase, white cells can irreversibly switch to the gray phase, and both white and gray cells can switch to and from the opaque/an opaque-like phase, respectively.<ref name="ReferenceC">{{cite journal | vauthors = Tao L, Du H, Guan G, Dai Y, Nobile CJ, Liang W, Cao C, Zhang Q, Zhong J, Huang G | display-authors = 6 | title = Discovery of a "white-gray-opaque" tristable phenotypic switching system in candida albicans: roles of non-genetic diversity in host adaptation | journal = PLOS Biology | volume = 12 | issue = 4 | pages = e1001830 | date = April 2014 | pmid = 24691005 | pmc = 3972085 | doi = 10.1371/journal.pbio.1001830 | doi-access = free }}</ref><ref name="Hemizygosity enables a mutational t">{{cite journal | vauthors = SLiang SH, Anderson MZ, Hirakawa MP, Wang JM, Frazer C, Alaalm LM, Thomson GJ, Ene IV, Bennett RJ | title = Hemizygosity enables a mutational transition governing fungal virulence and commensalism | journal = Cell Host Microbe | volume = 25 | issue = 3 | pages = 418–431.e6 | date = March 2019 | pmid = 30824263 | pmc = 6624852 | doi = 10.1016/j.chom.2019.01.005 }}</ref> Since it is often difficult to differentiate between white, opaque and gray cells phloxine B, a dye, can be added to the medium.<ref name="ReferenceC"/>

A potential regulatory molecule in the white to opaque switching is ''Efg1p'', a [[transcription factor]] found in the WO-1 strain that regulates dimorphism, and more recently has been suggested to help regulate phenotypic switching. ''Efg1p'' is expressed only in the white and not in the gray cell-type, and overexpression of ''Efg1p'' in the gray form causes a rapid conversion to the white form.<ref>{{cite journal | vauthors = Sonneborn A, Tebarth B, Ernst JF | title = Control of white-opaque phenotypic switching in Candida albicans by the Efg1p morphogenetic regulator | journal = Infection and Immunity | volume = 67 | issue = 9 | pages = 4655–4660 | date = September 1999 | pmid = 10456912 | pmc = 96790 | doi = 10.1128/IAI.67.9.4655-4660.1999 }}</ref><ref>{{cite journal | vauthors = Srikantha T, Tsai LK, Daniels K, Soll DR | title = EFG1 null mutants of Candida albicans switch but cannot express the complete phenotype of white-phase budding cells | journal = Journal of Bacteriology | volume = 182 | issue = 6 | pages = 1580–1591 | date = March 2000 | pmid = 10692363 | pmc = 94455 | doi = 10.1128/JB.182.6.1580-1591.2000 }}</ref><ref name="Hemizygosity enables a mutational t"/>

===Environmental stress===

Glucose starvation is a likely common environmental stress encountered by ''C. albicans'' in its natural habitat.<ref name="Guan2019">{{cite journal | vauthors = Guan G, Tao L, Yue H, Liang W, Gong J, Bing J, Zheng Q, Veri AO, Fan S, Robbins N, Cowen LE, Huang G | display-authors = 6 | title = Environment-induced same-sex mating in the yeast Candida albicans through the Hsf1-Hsp90 pathway | journal = PLOS Biology | volume = 17 | issue = 3 | pages = e2006966 | date = March 2019 | pmid = 30865631 | pmc = 6415874 | doi = 10.1371/journal.pbio.2006966 | doi-access = free }}</ref>  Glucose starvation causes an increase in [[reactive oxygen species|intracellular reactive oxygen]]. This stress can lead to mating between two individuals of the same mating type, an interaction that may be frequent in nature under stressful conditions.<ref name = Guan2019/>

===White-GUT switch===
A very special type of phenotypic switch is the white-GUT switch (Gastrointestinally-IndUced Transition). GUT cells are extremely adapted to survival in the digestive tract by metabolic adaptations to available nutrients in the digestive tract. The GUT cells live as commensal organisms and outcompete other phenotypes. The transition from white to GUT cells is driven by passage through the gut where environmental parameters trigger this transition by increasing the WOR1 expression.<ref>{{cite journal | vauthors = Pande K, Chen C, Noble SM | title = Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans commensalism | journal = Nature Genetics | volume = 45 | issue = 9 | pages = 1088–1091 | date = September 2013 | pmid = 23892606 | pmc = 3758371 | doi = 10.1038/ng.2710 }}</ref><ref>{{cite journal | vauthors = Noble SM, Gianetti BA, Witchley JN | title = Candida albicans cell-type switching and functional plasticity in the mammalian host | journal = Nature Reviews. Microbiology | volume = 15 | issue = 2 | pages = 96–108 | date = February 2017 | pmid = 27867199 | pmc = 5957277 | doi = 10.1038/nrmicro.2016.157 }}</ref>