Candida albicans

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Candida albicans

Candida albicans visualised using scanning electron

microscopy. Note the abundant hypal mass.

Scientific classification

Kingdom: Fungi

Division: Ascomycota

Class: Saccharomycetes

Order: Saccharomycetales

Family: Saccharomycetaceae

Genus: Candida

Species: C. albicans

Binomial name

Candida albicans
 (C.P.Robin) Berkhout (1923)

Synonyms

Candida stellatoidea[1]

Monilia albicans [2]

Oidium albicans[3]

Candida albicans is a type of yeast that is a common member of the human gut flora. It does not
proliferate outside the human body.[4] It is detected in the gastrointestinal tract and mouth in 40-60%
of healthy adults.[5][6] It is usually a commensal organism, but can
become pathogenic in immunocompromised individuals under a variety of conditions.[6][7] It is one of
the few species of the Candida genus that causes the human infection candidiasis, which results
from an overgrowth of the fungus.[6][7] Candidiasis is for example often observed in HIV-infected
patients.[8]

Different morphological forms of Candida albicans: the scale bar is 50 m.

C. albicans is the most common fungal species isolated from biofilms either formed on (permanent)
implanted medical devices or on human tissue.[9][10] C. albicans, together with C. tropicalis, C.
parapsilosis and C. glabrata, is responsible for 5090% of all cases of candidiasis in humans.[7][11][12] A
mortality rate of 40% has been reported for patients with systemic candidiasis due to C.
albicans.[13] Estimates range from 2800 to 11200 deaths caused annually in the USA due to C.
albicans causes candidiasis.[14]
C. albicans is commonly used as a model organism for biology. It is generally referred to as
a dimorphic fungus since it grows both as yeast and filamentous cells. However it has several
different morphological phenotypes. C. albicans was for a long time considered an obligate diploid
organism without a haploid stage. This is however not the case. Next to a haploid stage C.
albicans can also exist in a tetraploid stage. The latter is formed when diploid C. albicans cells mate
when they are in the opaque form.[15] The diploid genome size is approximately 29Mb, and up to 70%
of the protein coding genes have not yet been characterized.[16] C. albicans is easily cultured in the
lab and can be studied both in vivo as in vitro. Depending on the media different studies can be done
as the media influences the morphological state of C. albicans. A special type of medium is
CHROMagar Candida which can be used to identify different species of candida.[17][18]

Contents
[hide]

1Etymology
 2Genome
3Morphology
o 3.1Yeast to hyphae switching
o 3.2High frequency switching
o 3.3White to opaque switching
o 3.4White-GUT switch
4Role in disease
o 4.1Superficial and local infections
o 4.2Systemic infections
o 4.3Economic implications
5Proteins important for pathogenesis
o 5.1Hwp1
o 5.2Slr1
o 5.3Candidalysin
6Genetic and genomic tools
o 6.1Selection markers
o 6.2Full sequence genome
o 6.3ORFeome project
o 6.4CIp10 integrative plasmid
o 6.5Candida two-hybrid (C2H) system
o 6.6Microarrays
o 6.7GRACE library
7Application in engineering
8Treatment
9Notable C. albicans researchers
10See also
11References
12Further reading
13External links

Etymology[edit]
Candida albicans can be seen as a tautology. Candida comes from the Latin word candidus,
meaning white. Albicans itself is the present participle of the Latin word albic, meaning becoming
white. This leads to white becoming white, making it a tautology.
It is often shortly referred to as thrush, candidiasis or candida. More than hundred synonyms have
been used to describe C. albicans.[2][19] Over 200 species have been described within the candida
genus. The oldest reference to thrush, most likely caused by C. albicans, dates back to 400 B.C.
in Hippocrates' work Of the Epidemics describing oral candidiasis.[20][2]

Genome[edit]

Candida albicans growing on Sabouraud agar

The genome of C. albicans is almost 16Mb for the haploid size (28Mb for the diploid stage) and
consists out of 8 sets of chromosome pairs called chr1A, chr2A, chr3A, chr4A, chr5A, chr6A, chr7A
and chrRA. The second set (C. albicans is diploid) has similar names but with a B at the end. Chr1B,
chr2B, ... and chrRB. The whole genome contains 6198 Open Reading Frames (ORFs). 70% of
these ORFs have not yet been characterized. The whole genome has been sequenced making it
one of the first fungi to be completely sequenced (next to Saccharomyces
cerevisiae and Schizosaccharomyces pombe).[16][8] All open reading frames (ORFs) are also available
in gateway adapted vectors. Next to this ORFeome there is also the availability of a GRACE (gene
replacement and conditional expression) library to study essential genes in the genome of C.
albicans.[21][22] The most commonly used strains to study C. albicans are the WO-1 and SC5314
strains. The WO-1 strain is known to switch between white-opaque form with higher frequency while
the SC5314 strain is the strain used for gene sequence reference.[23]
One of the most important features of the C. albicans genome is the high heterozygosity. At the base
of this heterozygosity lies the occurrence of numeric and structural chromosomal rearrangements
and changes as means of generating genetic diversity by chromosome length polymorphisms
(contraction/expansion of repeats), reciprocal translocations, chromosome deletions,
Nonsynonymous single-base polymorphisms and trisomy of individual chromosomes.
These karyotypic alterations lead to changes in the phenotype, which is an adaptation strategy of
this fungus. These mechanisms are further being explored with the availability of the complete
analysis of the C. albicans genome.[24][25][26]
An unusual feature of the Candida genus is that in many of its species (including C. albicans and C.
tropicalis, but not, for instance, C. glabrata) the CUG codon, which normally specifies leucine,
specifies serine in these species. This is an unusual example of a departure from the
standard genetic code, and most such departures are in start codons or,
for eukaryotes, mitochondrial genetic codes.[27][28][29] This alteration may, in some environments, help
these Candida species by inducing a permanent stress response, a more generalized form of
the heat shock response.[30] However this different codon usage makes it more difficult to study C.
albicans protein-protein interactions in the model organism S. cerevisiae. To overcome this problem
a C. albicans specific two-hybrid system was developed.[31]
The genome of C. albicans is highly dynamic, contributed by the different CUG translation, and this
variability has been used advantageously for molecular epidemiological studies and population
studies in this species. The genome sequence has allowed for identifying the presence of
a parasexual cycle (no detected meiotic division) in C. albicans.[32] This study of the evolution of
sexual reproduction in six Candida species found recent losses in components of the major meiotic
crossover-formation pathway, but retention of a minor pathway.[32] The authors suggested that
if Candida species undergo meiosis it is with reduced machinery, or different machinery, and
indicated that unrecognized meiotic cycles may exist in many species. In another evolutionary study,
introduction of partial CUG identity redefinition (from Candida species) into Saccharomyces
cerevisiae clones caused a stress response that negatively affected sexual reproduction. This CUG
identity redefinition, occurring in ancestors of Candida species, was thought to lock these species
into a diploid or polyploid state with possible blockage of sexual reproduction.[33]

Morphology[edit]
C. albicans exhibits a wide range of different morphological phenotypes due to phenotypic switching
and bud to hypha transition. The yeast to hyphae transition 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.[34][35] Switching in C. albicans is often, but not always, influenced by
environmental conditions such as the level of CO2, anaerobic conditions, medium used and
temperature.[36]

An opaque colony of C. albicans growing as yeast like cells with on top filamentous like C. albicans cells

Yeast to hyphae switching[edit]

Although often referred to as dimorphic, C. albicans is in fact polyphenic (often also referred to
as pleomorphic).[37] When cultured in standard yeast laboratory medium, C. albicans grows as ovoid
"yeast" cells. However, mild environmental changes in temperature, CO2, nutrients and pH can result
in a morphological shift to filamentous growth.[38][39] 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.[40][41][42] 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.[43]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). Candida albicans can also form Chlamydospores, 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.[44]
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.[45][46]

Round, white-phase and elongated, opaque-phase Candida albicans cells: the scale bar is 5 m.
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[edit]

Besides the well studied yeast to hyphae transition other switching systems have been
described.[47] One such system is the "high frequency switching" system. During this switching
different cellular morphologies (phenotypes) are generated spontaneously. This type of switching
does not occur en masse, represents a variability system and it happens independently from
environmental conditions.[48] The strain 3153A produces at least seven different colony
morphologies.[49][50][51] 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. While several genes that are expressed differently in different colony morphologies have
been identified, some recent efforts focus on what might control these changes. Further, whether a
potential molecular link between dimorphism and phenotypic switching occurs is a tantalizing
question.[52] Being able to switch through so many different (morphological) phenotypes makes C.
albicans able to grow in different environments and this both as a commensal and as a pathogen.[53]
In the 3153A strain, a gene called SIR2 (for silent information regulator), which seems to be
important for phenotypic switching, has been found. SIR2 was originally found in Saccharomyces
cerevisiae (brewer's yeast), where it is involved in chromosomal silencinga 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 chromosomes). 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. 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.
White to opaque switching[edit]
Next to the dimorphism and the first described high frequency switching system C.
albicans undergoes another high frequency switching process called white to opaque switching,
which is another phenotypic switching process in C. albicans. It was the second high-frequency
switching system discovered in C. albicans.[54] The white to opaque switching is
an epigenetic switching system.[55] 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 from white cells to opaque cells is important for the virulence and
the mating process of C. albicans as the opaque form is the mating competent form, being a million
times more efficient in mating compared to the white type.[56][55][57] 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 (a1-2) that inhibits the expression of WOR1.[58] 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
tristable phenotypic switching system. Since it is often difficult to differentiate between white, opaque
and gray cells phloxine B, a dye, can be added to the medium.[53]
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.[59][60]
White-GUT switch[edit]
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.[61][62]

Role in disease[edit]
Main article: Candidiasis
Candida is found worldwide but most commonly compromises immunocompromised individuals
diagnosed with serious diseases such as HIV and cancer. Candida are ranked as one of the most
common groups of organisms that cause nosocomial infections. Especially high risk individuals are
patients that have recently undergone surgery, a transplant or are in the Intensive Care Units
(ICU),[63] Candida albicans infections is the top source of fungal infections in critically ill or otherwise
immuncompromised patients.[64] These patients predominantly develop oropharyngeal or thrush
candidiasis, which can lead to malnutrition and interfere with the absorption of
medication.[65] Methods of transmission include mother to infant through childbirth, people-to-people
acquired infections that most commonly occur in hospital settings where immunocompromised
patients acquire the yeast from healthcare workers and has a 40% incident rate. Men can become
infected after having sex with a woman that has an existing vaginal yeast infection.[63] Parts of the
body that are commonly infected include the skin, genitals, throat, mouth, and
blood.[66] Distinguishing features of vaginal infection include discharge, and dry and red appearance
of vaginal mucosa or skin. Candida continues to be the fourth most commonly isolated organism in
bloodstream infections.[67]
Superficial and local infections[edit]
It commonly occurs, as a superficial infection, on mucous membranes in the mouth or vagina. Once
in their life around 75% of women will suffer from vulvovaginal candidiasis (VVC) and about 90% of
these infections are caused by C. albicans. It however may also affect a number of other regions.
For example, higher prevalence of colonization of C. albicans was reported in young individuals
with tongue piercing, in comparison to unpierced matched individuals.[68] To infect host tissue, the
usual unicellular yeast-like form of C. albicans reacts to environmental cues and switches into an
invasive, multicellular filamentous form, a phenomenon called dimorphism.[69] In addition, an
overgrowth infection is considered superinfection, usually applied when an infection become
opportunistic and very resistant to antifungals. It then becomes suppressed by antibiotics. The
infection is prolonged when the original sensitive strain is replaced by the antibiotic-resistant strain.[70]
Candidiasis is known to cause GI symptoms particularly in immunocompromised patients or those
receiving steroids (e.g. to treat asthma) or antibiotics. Recently, there is emerging literature that an
overgrowth of fungus in the small intestine of non-immunocompromised subjects may cause
unexplained GI symptoms. Small intestinal fungal overgrowth (SIFO) is characterized by the
presence of excessive number of fungal organisms in the small intestine associated with
gastrointestinal (GI) symptoms. The most common symptoms observed in these patients were
belching, bloating, indigestion, nausea, diarrhea, and gas. The underlying mechanism(s) that
predisposes to SIFO is unclear. Further studies are needed; both to confirm these observations and
to examine the clinical relevance of fungal overgrowth.[6][7][71]
Systemic infections[edit]
Systemic fungal infections (fungemias) including those by C. albicans have emerged as important
causes of morbidity and mortality in immunocompromised patients (e.g., AIDS,
cancer chemotherapy, organ or bone marrow transplantation). C. albicans often forms biofilms inside
the body. Such C. albicans biofilms may form on the surface of implantable medical devices or
organs. In these biofilms it is often found together with Staphylococcus aureus.[72][73][9][10] Such
multispecies infections lead to higher mortalities.[74] In addition hospital-acquired infections by C.
albicans have become a cause of major health concerns.[75][8] Especially once candida cells are
introduced in the bloodstream a high mortality, up to 40-60% can occur.[8][76]
Although Candida albicans is the most common cause of candidemia, there has been a decrease in
the incidence and an increases isolation of non-albicans species of Candida in recent
years.[77] Preventive measures include keeping a healthy lifestyle including good nutrition, proper
nutrition, and careful antibiotic use.
Economic implications[edit]
Given the fact that candidiasis is the fourth (to third) most frequent hospital acquired infection
worldwide it leads to immense financial implications. Approximately 60000 cases of systemic
candidiasis each year in the USA alone lead up to a cost to be between $24 billion.[78] The total
costs for candidiasis are among the highest compared to other fungal infections due to the high
prevalence.[79] The immense costs are partly explained by a longer stay in the intensive care unit or
hospital in general. An extended stay for up to 21 more days compared to non infected patients is
not uncommon.[80]

Proteins important for pathogenesis[edit]

Hwp1[edit]
Main article: Hwp1
Hwp1 stands for Hyphal wall protein 1. Hwp1 is a mannoprotein located on the surface of the
hyphae in the hyphal form of Candida albicans. Hwp1 is a mammalian transglutaminase substrate.
This host enzyme allows Candida albicans to attach stably to host epithelial cells.[81] Adhesion
of Candida albicans to host cells is an essential first step in the infection process for colonization and
subsequent induction of mucosal infection.
Slr1[edit]
RNA-binding protein Slr1 was recently discovered to play a role in instigating the hyphal formation
and virulence in C. albicans.[82]
Candidalysin[edit]
Candidalysin is a cytolytic 31-amino acid -helical peptide toxin that is released during hyphal
formation. It contributes to virulence during mucosal infections.[83]

Genetic and genomic tools[edit]

Due to his nature as a model organism, being an important human pathogen and the alternative
codon usage (CUG translated into serine rather than leucine), several specific projects and tools
have been created to study C. albicans.[8]. The diploid nature and the absence of a sexual cycle
however makes it a hard to study organism. In the last 20 years however many systems have been
developed to study C. albicans in a more in depth genetic level.
Selection markers[edit]
The most used selection markers in C. albicans are the CaNAT1 resistance marker (confers
resistance against nourseothricin) and MPAr or IMH3r (confers resistance to mycophenolic acid)[84].
Next to the above mentioned selection makers a few auxotrophic strains were generated to work
with auxotrophic makers. The URA3 marker (URA3 blaster method) is an often used strategy in
uridine auxotrophic strains, however studies have shown that differences in URA3 position in the
genome can be involved in the pathogeny of C. albicans[85]. Besisdes the URA3 selection one can
also use the histidine, leucine and arginine autotrophy. The advantage of using those autotrophies
lies in the fact that they exhibit wild-type or nearly wild-type virulence in a mouse model compared to
the URA3 system[86]. One application of the leucine, arginine and histidine autotrophy is for example
the candida two hybrid system[87]
Full sequence genome[edit]
The full genome of C. albicans has been sequenced and made publicly available in a candida
database. The heterozygous diploid strain used for this full genome sequence project is the
laboratory strain SC5314. The sequencing was done using a whole-genome shotgun approach.[88][89]
ORFeome project[edit]
Every predicted ORF has been created in a gateway adapted vector (pDONR207) and made
publicly available. The vectors (plasmids) can be propagated in E.coli and grown on
LB+gentamicin medium. This way every ORF is readily available in an easy to use vector. Using the
gateway system it is possible to transfer the ORF of interest to any other gateway adapted vector for
further studies of the specific ORF.[90][22]
CIp10 integrative plasmid[edit]
Contrary to the yeast S. cerevisiae episomal plasmids do not stay stable in C. albicans. In order to
work with plasmids in C. albicans an integrative approach (plasmid integration into the genome) thus
has to be used. A second problem is that most plasmid transformations are rather inefficient in C.
albicans, however the CIp10 plasmid overcomes these problems and can be used with ease to
transform C. albicans in a very efficient way. The plasmid integrates inside the RP10 locus as
disruption of one RP10 allele does not seem to affect the viability and growth of C. albicans. Several
adaptations of this plasmid have been made after the original became available.[91][92]
Candida two-hybrid (C2H) system[edit]
Due to the aberrant codon usage of C. albicans it is less feasible to use the common host organism
(Saccharomyces cerevisiae) for two-hybrid studies. To overcome this problem a Candida
albicans two-hybrid (C2H) system was created. The strain SN152 that is auxotrophic for leucine,
arginine and histidine was used to create this C2H system. It was adapted by integrating a HIS1
reporter gene preceded by five LexAOp sequences. In the C2H system the bait plasmid (pC2HB)
contains the staphylococcus aureus LexA BD, while the prey plasmid (pC2HP) harbors the viral AD
VP16. Both plasmids are integrative plasmids since episomal plasmids do not stay stable in C.
 albicans. The reporter gene used in the system is the HIS1 gene. When proteins interact, the cells
will be able to grow on medium lacking histidine due to the activation of the HIS1 reporter gene.[31][8]
Microarrays[edit]
Both DNA and protein microarrays were designed to study DNA expression profiles and antibody
production in patients against C. albicans cell wall proteins.[93][94]
GRACE library[edit]
Using a tetracycline-regulatable promoter system a gene replacement and conditional expression
(GRACE) library was created for 1152 genes. By using the regulatable promoter and having deleted
1 of the alleles of the specific gene it was possible to discriminate between non-essential and
essential genes. Of the tested 1152 genes 567 showed to be essential. The knowledge on essential
genes can be used to discover novel antifungals.[95]

Application in engineering[edit]
Candida albicans has been used in combination with carbon nanotubes (CNT) to produce stable
electrically conductive bio-nano-composite tissue materials that have been used as temperature
sensing elements[96]

Treatment[edit]
Main article: Candidiasis Treatment
Treatment commonly includes:[97]

amphotericin B, echinocandin, or fluconazole for systemic infections

Nystatin for oral and esophageal infections
Clotrimazole for skin and genital yeast infections[98]
Important to note is that similar to antibiotic resistance, resistance to many anti-fungals is becoming
a big problem. New anti-fungals have to be developed to cope with this problem since only a limited
number of anti-fungals are available.[99][100]

Notable C. albicans researchers[edit]

Clarissa Nobile
David R. Soll
Neil A. R. Gow
Fred Sherman

See also[edit]

Fungi portal

Intestinal permeability
Torula yeast (Candida utilis)
Neonatal infection
codon usage