Candida albicans secreted aspartyl proteinases in virulence and pathogenesis

Abstract

Candida albicans is the most common fungal pathogen of humans and has developed an extensive repertoire of putative virulence mechanisms that allows successful colonization and infection of the host under suitable predisposing conditions. Extracellular proteolytic activity plays a central role in Candida pathogenicity and is produced by a family of 10 secreted aspartyl proteinases (Sap proteins). Although the consequences of proteinase secretion during human infections is not precisely known, in vitro, animal, and human studies have implicated the proteinases in C. albicans virulence in one of the following seven ways: (i) correlation between Sap production in vitro and Candida virulence, (ii) degradation of human proteins and structural analysis in determining Sap substrate specificity, (iii) association of Sap production with other virulence processes of C. albicans, (iv) Sap protein production and Sap immune responses in animal and human infections, (v) SAP gene expression during Candida infections, (vi) modulation of C. albicans virulence by aspartyl proteinase inhibitors, and (vii) the use of SAP-disrupted mutants to analyze C. albicans virulence. Sap proteins fulfill a number of specialized functions during the infective process, which include the simple role of digesting molecules for nutrient acquisition, digesting or distorting host cell membranes to facilitate adhesion and tissue invasion, and digesting cells and molecules of the host immune system to avoid or resist antimicrobial attack by the host. We have critically discussed the data relevant to each of these seven criteria, with specific emphasis on how this proteinase family could contribute to Candida virulence and pathogenesis.

FIG. 1.

Dendrogram displaying the relationship by sequence homology of the C. albicans Sap isoenzyme family. Three distinct groups are clustered within the family. Sap1 to Sap3 are up to 67% identical, and Sap4 to Sap6 are up to 89% identical, while Sap7 is only 20 to 27% identical to other Sap proteins. Sap9 and Sap10 both have C-terminal consensus sequences typical for GPI proteins and constitute the third distinct group. Similar Sap families exist in C. dubliniensis and C. tropicalis. Reprinted from reference with permission.

FIG. 2.

Schematic diagram illustrating the contribution of the various virulence attributes to C. albicans pathogenicity. C. albicans commonly colonizes the epithelial surface (stage 1) and causes superficial infections (stage 2), but under conditions when the host is compromised, the fungus establishes deep-seated infections (stage 3) by penetrating further into the epithelial tissue. Occasionally, C. albicans causes disseminated infections (stage 4), which allow the fungus to colonize and infect other host tissues and can be fatal. This infective process involves numerous virulence attributes including adhesins, hydrolytic enzyme production (Sap proteins, phospholipases, and lipases), hypha formation, and phenotypic switching. Sap2 (and possibly other Sap proteins) is known to degrade many human proteins, including mucin, extracellular matrix proteins, numerous immune system molecules, endothelial cell proteins, and coagulation and clotting factors. Therefore, the action of Sap proteins could be involved in all four stages of infection and probably greatly enhances the pathogenic ability of C. albicans. Modified from reference with permission.