Candida albicans
Encyclopedia
Candida albicans is a diploid fungus
that grows both as yeast
and filamentous
cells and a causal agent of opportunistic
oral and genital infections in humans. Systemic fungal infections (fungemia
s) including those by C. albicans have emerged as important causes of morbidity and mortality
in immunocompromise
d patients (e.g., AIDS
, cancer chemotherapy
, organ or bone marrow
transplantation). C. albicans biofilms may form on the surface of implantable medical devices. In addition, hospital-acquired infections
by C. albicans have become a cause of major health concerns.
C. albicans is commensal and a constituent of the normal gut flora
comprising microorganisms that live in the human mouth and gastrointestinal tract
. C. albicans lives in 80% of the human population without causing harmful effects, although overgrowth of the fungus results in candidiasis
(candidosis). Candidiasis is often observed in immunocompromise
d individuals such as HIV
-infected patients. A common form of candidiasis restricted to the mucosal membranes in mouth or vagina is thrush, which is usually easily cured in people who are not immunocompromised. For example, higher prevalence
of colonization of C. albicans was reported in young individuals with tongue
piercing
, in comparison to non-tongue-pierced matched individuals. 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
.
One of the most important features of the C. albicans genome is the occurrence of numeric and structural chromosomal
rearrangements as means of generating genetic diversity, named chromosome length polymorphisms (contraction/expansion of repeats), reciprocal translocations
, chromosome deletions
and trisomy
of individual chromosomes. These karyotypic
alterations lead to changes in the phenotype, which is an adaptation
strategy of this fungus. These mechanisms will be better understood with the complete analysis of the C. albicans genome.
The C. albicans genome for strain SC5314 was sequenced
at the Stanford DNA Sequencing and Technology Center. The genome of the WO1 strain was sequenced by the Broad Institute of MIT and Harvard
.
The sequencing of the C. albicans genome and subsequently of the genomes of several other medically relevant Candida species has profoundly and irreversibly changed the way Candida species are now investigated and understood. The C. albicans genome sequencing effort was launched in October 1996. Successive releases of the sequencing data and genome assemblies have occurred in the last 10 years, culminating in the release of the diploid assembly 19, which provided a haploid version of the genome along with data on allelic regions in the genome. A refined assembly 20 with the eight assembled C. albicans chromosomes was released in the summer of 2006. Importantly, the availability of sequencing data prior to the completion of the genome sequence has made it possible to start C. albicans post-genomics early on. In this regard, genome databases have been made available to the research community providing different forms of genome annotation. These have been merged in a community-based annotation hosted by the Candida Genome Database. The availability of the genome sequence has paved the way for the implementation of post-genomic approaches to the study of C. albicans: macroarrays and then microarrays have been developed and used to study the C. albicans transcriptome
; proteomics has also been developed and complements transcriptional analyses; furthermore, systematic approaches are becoming available to study the contribution of each C. albicans gene in different contexts. Other Candida genome sequences have been, or are being, determined: C. glabrata
, C. dubliniensis, C. parapsilosis, C. guilliermondii, C. lusitaniae, and C. tropicalis
. These species will soon enter the post-genomic era as well and provide interesting comparative data. The genome sequences obtained for the different Candida species along with those of non-pathogenic hemiascomycetes provide a wealth of knowledge on the evolutionary processes that shaped the hemiascomycete group, as well as those that may have contributed to the success of different Candida species as pathogens.
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 universal genetic code (most such departures are in start codons or, for eukaryotes, mitochondrial genetic codes). This alteration may help these Candida species (in some environments) by inducing a permanent stress response - a more generalized form of the heat shock
response.
The genome of C. albicans is highly dynamic, and this variability has been used advantageously for molecular epidemiological studies of C. albicans and population studies in this species. The genome sequence has allowed for identifying the presence of a parasexual cycle (no meiotic division
) in C. albicans. This parasexual cycle is under the control of mating-type loci and switching between white and opaque phenotypes. Investigating the role the mating process plays in the dynamics of the C. albicans population or in other aspects of C. albicans biology and pathogenicity will undoubtedly represent an important focus for future research. A similar lack of meiosis was found in Saccharomyces cerevisiae
altered to use the same genetic code as C. albicans.
In a process that superficially resembles dimorphism
, C. albicans undergoes a process called phenotypic switching
, in which different cellular morphologies are generated spontaneously. One of the classically studied strains that undergoes phenotypic switching is WO-1, which consists of two phases: one that grows as round cells in smooth white colonies and one that is rod-like and grows as flat gray colonies. The other strain known to undergo switching is 3153A; this strain produces at least seven different colony morphologies. In both the WO-1 and 3153A 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 gene
s that are expressed
differently in different colony morphologies have been identified, some recent efforts focus on what might control these changes. Further, whether there is a potential molecular link between dimorphism and phenotypic switching is a tantalizing question.
In the 3153A strain, a gene called SIR2 (for silent information regulator) has been found that seems to be important for phenotypic switching. SIR2
was originally found in Saccharomyces cerevisiae
(brewer's yeast), where it is involved in 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 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.
Another potential regulatory molecule 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.
So far, very few data say that dimorphism and phenotypic switching use common molecular components. However, it is not inconceivable that phenotypic switching may occur in response to some change in the environment as well as being a spontaneous event. How SIR2 itself is regulated in S. cerevisiae may yet provide clues as to the switching mechanisms of C. albicans.
result in two proteins that differ in one or several amino acids that may confer functional differences for each protein. This situation considerably increases the number of different proteins encoded by the genome.
Fungus
A fungus is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds , as well as the more familiar mushrooms. These organisms are classified as a kingdom, Fungi, which is separate from plants, animals, and bacteria...
that grows both as yeast
Yeast
Yeasts are eukaryotic micro-organisms classified in the kingdom Fungi, with 1,500 species currently described estimated to be only 1% of all fungal species. Most reproduce asexually by mitosis, and many do so by an asymmetric division process called budding...
and filamentous
Hypha
A hypha is a long, branching filamentous structure of a fungus, and also of unrelated Actinobacteria. In most fungi, hyphae are the main mode of vegetative growth, and are collectively called a mycelium; yeasts are unicellular fungi that do not grow as hyphae.-Structure:A hypha consists of one or...
cells and a causal agent of opportunistic
Opportunistic infection
An opportunistic infection is an infection caused by pathogens, particularly opportunistic pathogens—those that take advantage of certain situations—such as bacterial, viral, fungal or protozoan infections that usually do not cause disease in a healthy host, one with a healthy immune system...
oral and genital infections in humans. Systemic fungal infections (fungemia
Fungemia
-Pathogens:The most commonly known pathogen is Candida albicans, causing roughly 70% of fungemias, followed by Candida glabrata with 10%, Aspergillus with 1% and Saccharomyces as the fourth most common. However, the frequency of infection by C. glabrata, Saccharomyces boulardii, Candida tropicalis,...
s) including those by C. albicans have emerged as important causes of morbidity and mortality
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
in immunocompromise
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
d patients (e.g., AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
, cancer chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, organ or bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
transplantation). C. albicans biofilms may form on the surface of implantable medical devices. In addition, hospital-acquired infections
Nosocomial infection
A nosocomial infection , also known as a hospital-acquired infection or HAI, is an infection whose development is favoured by a hospital environment, such as one acquired by a patient during a hospital visit or one developing among hospital staff...
by C. albicans have become a cause of major health concerns.
C. albicans is commensal and a constituent of the normal gut flora
Gut flora
Gut flora consists of microorganisms that live in the digestive tracts of animals and is the largest reservoir of human flora. In this context, gut is synonymous with intestinal, and flora with microbiota and microflora....
comprising microorganisms that live in the human mouth and gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
. C. albicans lives in 80% of the human population without causing harmful effects, although overgrowth of the fungus results in candidiasis
Candidiasis
Thrush redirects here. For the hoof infection see Thrush .Candidiasis or thrush is a fungal infection of any of the Candida species , of which Candida albicans is the most common...
(candidosis). Candidiasis is often observed in immunocompromise
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
d individuals such as HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
-infected patients. A common form of candidiasis restricted to the mucosal membranes in mouth or vagina is thrush, which is usually easily cured in people who are not immunocompromised. For example, higher prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of colonization of C. albicans was reported in young individuals with tongue
Tongue
The tongue is a muscular hydrostat on the floors of the mouths of most vertebrates which manipulates food for mastication. It is the primary organ of taste , as much of the upper surface of the tongue is covered in papillae and taste buds. It is sensitive and kept moist by saliva, and is richly...
piercing
Tongue piercing
A tongue piercing is a body piercing usually done directly through the center of the tongue, and is the most popular piercing site in the western world after the ear and nostril.-History and culture:...
, in comparison to non-tongue-pierced matched individuals. To infect host tissue, the usual unicellular
Unicellular organism
A unicellular organism, also known as a single-celled organism is an organism that consists of only one cell, in contrast to a multicellular organism that consists of multiple cells. Historically simple single celled organisms have sometimes been referred to as monads Prokaryotes, most protists,...
yeast-like form of C. albicans reacts to environmental cues and switches into an invasive, multicellular filamentous form, a phenomenon called dimorphism
Dimorphic fungi
Dimorphic fungi are fungi which can exist as mold/hyphal/filamentous form or as yeast. An example is Penicillium marneffei:* At room temperature, it grows as a mold.* At body temperature, it grows as a yeast....
.
Genome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
rearrangements as means of generating genetic diversity, named chromosome length polymorphisms (contraction/expansion of repeats), reciprocal translocations
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
, chromosome deletions
Genetic deletion
In genetics, a deletion is a mutation in which a part of a chromosome or a sequence of DNA is missing. Deletion is the loss of genetic material. Any number of nucleotides can be deleted, from a single base to an entire piece of chromosome...
and trisomy
Trisomy
A trisomy is a type of polysomy in which there are three copies, instead of the normal two, of a particular chromosome. A trisomy is a type of aneuploidy .-Description and causes:...
of individual chromosomes. These karyotypic
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
alterations lead to changes in the phenotype, which is an adaptation
Adaptation
An adaptation in biology is a trait with a current functional role in the life history of an organism that is maintained and evolved by means of natural selection. An adaptation refers to both the current state of being adapted and to the dynamic evolutionary process that leads to the adaptation....
strategy of this fungus. These mechanisms will be better understood with the complete analysis of the C. albicans genome.
The C. albicans genome for strain SC5314 was sequenced
DNA sequencing
DNA sequencing includes several methods and technologies that are used for determining the order of the nucleotide bases—adenine, guanine, cytosine, and thymine—in a molecule of DNA....
at the Stanford DNA Sequencing and Technology Center. The genome of the WO1 strain was sequenced by the Broad Institute of MIT and Harvard
Broad Institute
The Broad Institute is a genomic medicine research center located in Cambridge, Massachusetts, United States. Although it is independently governed and supported as a 501 nonprofit research organization, the institute is formally affiliated with the Massachusetts Institute of Technology, Harvard...
.
The sequencing of the C. albicans genome and subsequently of the genomes of several other medically relevant Candida species has profoundly and irreversibly changed the way Candida species are now investigated and understood. The C. albicans genome sequencing effort was launched in October 1996. Successive releases of the sequencing data and genome assemblies have occurred in the last 10 years, culminating in the release of the diploid assembly 19, which provided a haploid version of the genome along with data on allelic regions in the genome. A refined assembly 20 with the eight assembled C. albicans chromosomes was released in the summer of 2006. Importantly, the availability of sequencing data prior to the completion of the genome sequence has made it possible to start C. albicans post-genomics early on. In this regard, genome databases have been made available to the research community providing different forms of genome annotation. These have been merged in a community-based annotation hosted by the Candida Genome Database. The availability of the genome sequence has paved the way for the implementation of post-genomic approaches to the study of C. albicans: macroarrays and then microarrays have been developed and used to study the C. albicans transcriptome
Transcriptome
The transcriptome is the set of all RNA molecules, including mRNA, rRNA, tRNA, and other non-coding RNA produced in one or a population of cells.-Scope:...
; proteomics has also been developed and complements transcriptional analyses; furthermore, systematic approaches are becoming available to study the contribution of each C. albicans gene in different contexts. Other Candida genome sequences have been, or are being, determined: C. glabrata
Candida glabrata
Candida glabrata is a haploid yeast of the genus Candida, previously known as Torulopsis glabrata. This species of yeast is non-dimorphic and no mating activity has been observed. Until recently, C. glabrata was thought to be a primarily non-pathogenic organism. However, with the ever increasing...
, C. dubliniensis, C. parapsilosis, C. guilliermondii, C. lusitaniae, and C. tropicalis
Candida tropicalis
Candida tropicalis is a species of yeast in the genus Candida. It is easily recognized as a common medical yeast pathogen, existing as part of the normal human flora.-External links:*...
. These species will soon enter the post-genomic era as well and provide interesting comparative data. The genome sequences obtained for the different Candida species along with those of non-pathogenic hemiascomycetes provide a wealth of knowledge on the evolutionary processes that shaped the hemiascomycete group, as well as those that may have contributed to the success of different Candida species as pathogens.
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 universal genetic code (most such departures are in start codons or, for eukaryotes, mitochondrial genetic codes). This alteration may help these Candida species (in some environments) by inducing a permanent stress response - a more generalized form of the heat shock
Heat shock
In biochemistry, heat shock is the effect of subjecting a cell to a higher temperature than that of the ideal body temperature of the organism from which the cell line was derived.-Heat shock response:...
response.
The genome of C. albicans is highly dynamic, and this variability has been used advantageously for molecular epidemiological studies of C. albicans and population studies in this species. The genome sequence has allowed for identifying the presence of a parasexual cycle (no meiotic division
Meiosis
Meiosis is a special type of cell division necessary for sexual reproduction. The cells produced by meiosis are gametes or spores. The animals' gametes are called sperm and egg cells....
) in C. albicans. This parasexual cycle is under the control of mating-type loci and switching between white and opaque phenotypes. Investigating the role the mating process plays in the dynamics of the C. albicans population or in other aspects of C. albicans biology and pathogenicity will undoubtedly represent an important focus for future research. A similar lack of meiosis was found in Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
altered to use the same genetic code as C. albicans.
Dimorphism
Although often referred to as “dimorphic”, C. albicans is in fact polyphenic. When cultured in standard yeast laboratory medium C. albicans grows as ovoid “yeast” cells. However, mild environmental changes in temperature and pH can result in a morphological shift to pseudohyphal growth. Pseudohyphae share many similarities with yeast cells but their role during candidiasis remains unknown. When C. albicans cells are grown in medium which mimic the physiological environment of a human host, they grow as “true” hyphae. The ability of C. albicans to form hyphae has been proposed as a virulence factor as these structures are often observed invading tissue and C. albicans strains which are unable to form hyphae are defective in causing infection.Sexual dimorphism
Sexual dimorphism is a phenotypic difference between males and females of the same species. Examples of such differences include differences in morphology, ornamentation, and behavior.-Examples:-Ornamentation / coloration:...
, C. albicans undergoes a process called phenotypic switching
Phenotypic switching
Phenotypic switching is switching between two cell-types. An example is Candida albicans, which, when it infects host tissue, switches from the usual unicellular yeast-like form of into an invasive, multicellular filamentous form. This switching between two cell-types is known as...
, in which different cellular morphologies are generated spontaneously. One of the classically studied strains that undergoes phenotypic switching is WO-1, which consists of two phases: one that grows as round cells in smooth white colonies and one that is rod-like and grows as flat gray colonies. The other strain known to undergo switching is 3153A; this strain produces at least seven different colony morphologies. In both the WO-1 and 3153A 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 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s that are expressed
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
differently in different colony morphologies have been identified, some recent efforts focus on what might control these changes. Further, whether there is a potential molecular link between dimorphism and phenotypic switching is a tantalizing question.
In the 3153A strain, a gene called SIR2 (for silent information regulator) has been found that seems to be important for phenotypic switching. SIR2
Sir2
Sir2 was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied...
was originally found in Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
(brewer's yeast), where it is involved in chromosomal silencing—a form of transcriptional regulation
Transcriptional regulation
Transcriptional regulation is the change in gene expression levels by altering transcription rates. -Regulation of transcription:Regulation of transcription controls when transcription occurs and how much RNA is created...
, in which regions of the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
are reversibly inactivated by changes in chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
structure (chromatin is the complex of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
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.
Another potential regulatory molecule is Efg1p, a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
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.
So far, very few data say that dimorphism and phenotypic switching use common molecular components. However, it is not inconceivable that phenotypic switching may occur in response to some change in the environment as well as being a spontaneous event. How SIR2 itself is regulated in S. cerevisiae may yet provide clues as to the switching mechanisms of C. albicans.
Heterozygosity
The heterozygosity of the Candida genome exceeds that found in other genomes and is widespread among clinical isolates. Non-synonymous single base polymorphismsSingle nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
result in two proteins that differ in one or several amino acids that may confer functional differences for each protein. This situation considerably increases the number of different proteins encoded by the genome.
See also
- Torula yeastTorulaTorula is a species of yeast.-Use:Torula, in its inactive form , is widely used as a flavouring in processed foods and pet foods. It is produced from wood sugars, as a byproduct of paper production...
(Candida utilis) - CandidiasisCandidiasisThrush redirects here. For the hoof infection see Thrush .Candidiasis or thrush is a fungal infection of any of the Candida species , of which Candida albicans is the most common...
- Undecylenic acidUndecylenic acidUndecylenic acid is an organic unsaturated fatty acid derived from castor oil. It is the common name of the 10-undecenoic acid, . It is used in the manufacture of pharmaceuticals, cosmetics and perfumery, including antidandruff shampoos, antimicrobial powders and as a musk in perfumes and aromas...
(Castor oil derivative) for candida fungus infections. - Leaky gut syndromeLeaky gut syndromeLeaky gut syndrome is a proposed condition of an altered or damaged bowel lining. The term is used by some alternative medicine practitioners, but the syndrome is not a recognized diagnosis. It is hypothesized to be caused by increased permeability of the gut wall resulting from toxins, poor diet,...
for damage to the bowel or gut (increased permeability to gut wall or bowel lining).