Abstract
The association of secreted proteolytic activity with virulence in Candida albicans is a story that has developed over the past 40 years. From the earliest biochemical work which tacitly assumed that this major fungal pathogen secreted a single proteinase enzyme to the genomic revelation of a family of 10 genes encoding secreted aspartyl proteinases (Saps), the presumption has been that externally secreted C. albicans hydrolases of broad substrate specificity ought to contribute to the pathogenesis of disease. Many excellent studies, including reverse genetics and in vivo expression technologies, have contributed to detailed knowledge of the roles of the various SAP gene products in the pathogenesis of superficial and disseminated Candida infections (Naglik et al., 2004).
Now two papers in the present issue of Microbiology (Lermann & Morschhäuser, 2008; Naglik et al., 2008) force a rethink of the dogma that Saps are major virulence factors in C. albicans: at least for superficial infections and their ex vivo model, reconstituted human epithelium (RHE). In two laboratories, different experimental approaches with the same RHE model were used to measure gene expression in vivo. Only SAP5 (among SAP1–6) appeared to be activated significantly at any stage of infection. And both studies, using independently generated single and multiple mutants, showed that SAP1–6 did not play an important role in the invasion of RHE.
The coincidental appearance of the two papers in the same journal at the same time is a welcome event, since the main message from both studies is a resolution of the growing list of published discrepancies from experiments designed to indicate which of the Saps are important at what stages and in what types of infection. The candour of Naglik and colleagues is admirable in their acknowledgement of the error of their earlier work that showed sequential upregulation of SAP1, SAP3 and SAP6, with SAP2 and SAP8 expression detected only in late stages of RHE and oral infection. The two new publications concur that no Sap appears to play an essential role in mucosal invasion. The possibility of a nonessential contribution of Sap5 is left open. The role of SAP9, which was strongly upregulated in RHE and in human oral and vaginal samples (Naglik et al., 2008), remains unclear, but since Sap9 is not actively secreted by growing C. albicans (Naglik et al., 2004) it seems unlikely that this enzyme will have a redundant function similar to the other Sap family enzymes.