Candida species are not highly virulent microorganisms, instead, they are ubiquitous human commensals, primarily residing in the gastrointestinal tract without causing any harm. Especially C. albicans readily colonizes host epithelia and is probably harboured by most individuals at some stage in their lives. As an essentially opportunistic pathogen C. albicans needs an immunocompromised host to do more than just colonize the epithelial surface. In hosts with defects in cell-mediated immunity it commonly causes superficial infections of mucosae, skin and nails but rarely penetrates beyond such sites to invade into deeper tissue. Disseminated infections predominantly occur in severely immunocompromised, neutropenic patients, for example organ transplant recipients or cancer patients. Yet, since C. albicans is by far the most frequent yeast species causing infections in such debilitated patients, it is conceivable that it must possess traits that make this species better adapted than others to overcome the residual host barriers and cause disease3.
Adhesion to host tissues generally is a prerequisite for colonization of the host by infecting microorganisms. The adhesion of different Candida species to host tissue correlates with their relative virulence, C. albicans adhering far better than other Candida species or the apathogenic yeast Saccharomyces cerevisiae to epithelial and endothelial cells as well as to extracellular matrix proteins4. In addition, differences in relative virulence have also been observed in C. albicans strains with differing degrees of adherence, and spontaneous mutants defective in adherence to buccal epithelial cells are less virulent in animal models than the parent strain.
As C. albicans adheres to many different types of host surfaces, it probably also possesses a broad panel of adherence factors. Various adherence mechanisms have been described. A lectin-like interaction of C. albicans surface proteins with fucosyl or N-acetyl-glucosamine containing glycosides on epithelial cells seems to be involved in binding to mucosal surfaces, whereas protein-protein interactions have been implicated in adherence to endothelial cells and extracellular matrix proteins5. Several genes encoding putative adhesins have recently been cloned. The ALS gene family encodes C. albicans cell surface proteins, and expression of the ALSl gene in S. cerevisiae confers adherence to epithelial and endothelial cells upon this normally non-adherent yeast6,7. HWP1 codes for a hyphae-specific surface protein that serves as a substrate for mammalian transglutaminases and is necessary for stable attachment to human buccal epithelial cells8. The INT1 gene encodes an integrin-like protein necessary for adhesion to epithelial cells. In addition, INT1 is also necessary for hyphae formation, thus providing a linkage between two C. albicans virulence factors9.
One outstanding characteristic of C. albicans is its ability to switch from the budding yeast form to mycelial growth. Although many other Candida species are able to grow in chains of largely elongated cells called pseudohyphae, C. albicans and the recently described new species C. dubliniensis are the only ones that form true hyphae10. For a long time it was a widely held view that the yeast form is representative of the commensal stage of C. albicans colonizing epithelial surfaces whereas hyphae are the pathogenic, invasive form (Fig 1).
However, histopathological observations demonstrate that both yeasts and hyphae are found in infected tissue and sometimes C. albicans yeasts invade tissue without any hyphae formation. Therefore, it is certainly not correct to consider the mycelial form as the exclusive virulent form of C. albicans; rather it seems to be the ability to switch between the two growth forms that is necessary to establish infection. Hyphae adhere more strongly to host surfaces than yeast cells and may also be better adapted for tissue invasion, whereas dissemination through the bloodstream to other organs might be more readily accomplished by the smaller yeasts. In this respect it is interesting that both mutants unable to form hyphae as well as mutants derepressed for mycelial growth are avirulent11'12.
The yeast-hyphae transition is not the only morphological switch C. albicans is able to perform. The fungus can also undergo spontaneous or induced reversible switching between different types of cells which is easily detected by a characteristic appearance of the corresponding colonies on agar plates13. Many C. albicans strains have their own repertoire of switch phenotypes, the best characterized system being the white-opaque switching of strain WO-1. Switching to a different cell type involves changes in antigenicity, drug resistance and expression of virulence factors and may therefore be a prerequisite for the adaptation to different host niches or the evasion of host defense mechanisms14.
C. albicans produces secreted hydrolytic enzymes like phospholipases and proteinases. The ability of C. albicans to secrete aspartic proteinases has been known for a long time15 and linked to virulence by many investigators since the proteolytic activity of different Candida species is correlated with their relative virulence16 and since C. albicans strains with the highest proteinase production are also the most virulent in different experimental infection models17'18. Possible roles of the secreted aspartic proteinases in pathogenicity may include the supply with nitrogen15, the degradation of tissue barriers during invasion19'20, the evasion of host defense mechanisms21'22, or adhesion23. During the last years it became evident that C. albicans possesses a family of at least ten genes, SAPI-10, encoding aspartic proteinases24,25. Mutants in which single or multiple SAP genes are disrupted display reduced virulence in animal models of candidiasis26,27,28. The individual members of the SAP gene family are differentially regulated in vitro29,30,31 , suggesting that they are also induced in different host niches during infection.
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