Secreted aspartyl proteinases (Saps) contribute to the ability of Candida albicans to cause mucosal and disseminated infections. A model of vaginal candidiasis based on reconstituted human vaginal epithelium (RHVE) was used to study the expression and role of these C. albicans proteinases during infection and tissue damage of vaginal epithelium. Colonization of the RHVE by C. albicans SC5314 did not cause any visible epithelial damage 6 h after inoculation, although expression of SAP2, SAP9, and SAP10 was detected by reverse transcriptase PCR. However, significant epithelial damage was observed after 12 h, concomitant with the additional expression of SAP1, SAP4, and SAP5. Additional transcripts of SAP6 and SAP7 were detected at a later stage of the artificial infection (24 h). Similar SAP expression profiles were observed in three samples isolated from human patients with vaginal candidiasis. In experimental infection, secretion of antigens Sap1 to Sap6 by C. albicans was confirmed at the ultrastructural level by using polyclonal antisera raised against Sap1 to Sap6. Addition of the aspartyl proteinase inhibitors pepstatin A and the human immunodeficiency virus proteinase inhibitors ritonavir and amprenavir strongly reduced the tissue damage of the vaginal epithelia by C. albicans cells. Furthermore, SAP null mutants lacking either SAP1 or SAP2 had a drastically reduced potential to cause tissue damage even though SAP3, SAP4, and SAP7 were up-regulated in these mutants. In contrast the vaginopathic potential of mutants lacking SAP3 or SAP4 to SAP6 was not reduced compared to wild-type cells. These data provide further evidence for a crucial role of Sap1 and Sap2 in C. albicans vaginal infections.Although normally a commensal habitant of mucosal surfaces, Candida albicans frequently causes surface infections when certain host factors are imbalanced. Under certain circumstances these superficial infections may disseminate to cause serious systemic infections. Key virulence factors of C. albicans that appear to play major roles in the pathogenesis of this opportunistic fungus are the secreted aspartyl proteinases (Saps), which are encoded by 10 SAP genes. These genes are regulated differentially in vitro and in vivo during infection of three-dimensional models for oral and cutaneous candidiasis in infected tissue of mice and in patient samples (3, 10, 15). Therefore, it has been concluded that different SAP genes may have distinct roles at different times of the infection process and during different types of infection (15). For example, by use of SAP-deficient mutants, it has been shown that SAP1, SAP2, and SAP3 contribute significantly to tissue damage and invasion of oral epithelium and cutaneous epidermis (23, 25), while SAP4, SAP5, and SAP6 are important for systemic infections (12,22). Several studies dealing with proteinase secretion and proteinase activity have shown a clear correlation between the ability of C. albicans strains to secrete Saps and to cause disease (4,5,7,9). The expression and importance ...

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Secreted aspartic proteinases (Saps) are important virulence factors in different types of candidiasis caused by Candida albicans (C. albicans). The various isoenzymes are expected to fulfil different tasks during mucosal or disseminated infections. It could be shown that the introduction of the proteinase inhibitors like saquinavir and indinavir in the therapy of human immunodeficiency virus (HIV) infected patients has an effect on Sap activity in vitro as well as in vivo. Therefore, drugs like the HIV proteinase inhibitors could play an essential role in the treatment of candidiasis in the future, especially if further adapted to this target.

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