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Candida albicans, a diploid sexual fungus (a form of yeast) is the causal agent of opportunistic infections in humans, the most common being oral and vaginal infections. Systemic fungal infections have emerged as important causes of morbidity and mortality in immunocompromised patients (e.g., AIDS, cancer chemotherapy, organ or bone marrow transplantation). In addition, hospital-related infections in patients not previously considered at risk (e.g. patients on an intensive care unit) have become a cause of major health concern.
Among the many organisms that live in the human mouth and digestive tract is the yeast Candida albicans, which under normal circumstances lives in 80 percent of the human population with no harmful effects. However, overgrowth results in candidiasis. Candidiasis is often observed in immunocompromised individuals such as HIV-positive patients. Candidiasis also may occur in the blood and in the genital tract. Candidiasis is commonly known as "thrush", and is a common condition that is usually easily cured in people who are not immunocompromised. To infect host tissue, the usual unicellular yeast-like form of Candida albicans reacts to environmental cues and switches into an invasive, multicellular filamentous form. This switching between two cell-types is known as dimorphism.
In a process that superficially resembles dimorphism, Candida 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 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 genes that are expressed differently in different colony morphologies have been identified, some recent efforts have focussed on what might be controlling 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 Candida albicans SIR2 that is implicated in phenotypic switching suggests that it too has silent regions controlled by SIR2, in which the phenotype-specific genes may perhaps 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 there are few data that says 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 Candida albicans.
One of the most interesting features of the Candida 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 Candida albicans genome.
The Candida albicans genome is being sequenced at the Stanford DNA Sequencing and Technology Center . Funding for this project is provided by National Institute of Dental and Craniofacial Research and Burroughs-Wellcome Fund . A pilot sequencing program is also being carried on by The Sanger Center . Funding for this project is provided by Beowulf Genomics .
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