C albicans Cell Surface

The proteins displayed on the cell wall are obviously important as it is these cells that can be sensed and interact with host cells (Sohn et al., 2006a). Glycosylphosp hatidylinositol (GPI)-anchored proteins in the cell wall have also been investigated using proteomic approaches. Theoretically, C. albicans strain SC5314 could display 104 GPI-anchored proteins on its cell surface (De Groot et al., 2003). However, proteomic analysis of exponentially growing yeast cells demonstrated that only 14 cell wall proteins were found on the cell surface (12 GPI-anchored and 2 mildalkali sensitive proteins) (de Groot et al., 2004). Proteins identified include carbohydrate-active enzymes (chitinase, Crh11p, Pga4p, Phr1p, Scw1p), adhesins (Als1p and Als4p, Pga24), a superoxide dismutase (Sod4p), and some unknown function proteins (Ecm33.3p, Pir1p, Pga29p, Rbt5p, Ssr1p). One of these proteins, Ecm33.3p, has been demonstrated to be important for normal cell wall structure and interactions with host cells (Martinez-Lopez et al., 2006). Furthermore, two GPI-anchored proteases (Albrecht et al., 2006) and Als proteins (Hoyer, 2001; Sheppard et al., 2004) have been demonstrated to be involved in adhesion to host cells. Expression of the ALS gene family has been demonstrated to be differentially regulated during growth by GFP-promoter fusion experiments (Green et al., 2005b), with ALS1 gene expression associated with transfer into fresh medium and ALS7 showing a transient peak 2-3 h after movement into fresh medium. ALS3 expression increases were associated with formation of germ tubes. In vivo, in a mouse model of systemic disease, ALS1, 2, 3, 4, and 9 were all found to be expressed (Green et al., 2005a).

Proteomics have also been used to identify C. albicans proteins that bind to blood proteins, e.g. plasminogen (Crowe et al., 2003; Jong et al., 2003). Proteins identified include phosphoglycerate mutase, alcohol dehydrogenase, glyceraldehyde-3-phos-phate dehydrogenase, phosphoglycerate kinase, fructose bisphosphate aldolase (Fbalp), and enolase (Enolp), which were also found to be upregulated in proteomic studies examining yeast-hypha dimorphism (Pitarch et al., 2002; Choi et al., 2003; Ebanks et al., 2006). C. albicans is able to invade and transcytose brain microvascular endothelial cells without affecting monolayer intergrity (Jong et al., 2001), with plasmin-bound cells demonstrated to do this more easily (Jong et al., 2003).

A further proteomic approach, immunoproteomics, also been applied to identify immunogenic proteins of C. albicans (Pitarch et al., 2001; Fernandez-Arenas et al., 2004; Pitarch et al., 2004). This involves 2-D electrophoresis followed by Western blotting.

Proteomic analysis of immunogenic proteins in a mouse model of systemic candidiasis identified more than 31 immunoreactive proteins; including glycolytic enzymes, such as fructose bisphosphate aldolase, triose phosphate isomerase (Tpilp), glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, triose phosphate isomerase, enolase, and pyruvate kinase (Pitarch et al., 2001). Metabolic enzymes, such as methionine synthase, Imh3p, alcohol dehydrogenase and aconitase, and heat-shock proteins from the Hsp70 family were also identified as immunogenic. Different antibody profiles were identified for strains of mice with differing susceptibility to systemic C. albicans infection. Eno1p was the dominant immunogenic protein in BALB/c mice (most resistant), with the more susceptible mice having a stronger reaction to methionine synthase, Hsp70 proteins, and phosphoglycerate kinase (Pitarch et al., 2001).

Immunoproteomics with patient serum identified proteins including Hsp70s and Hsp90, enolase (Eno1p), pyruvate kinase (Cdc19p), pyruvate decarboxylase (Pdc11p), hexokinase, glucose-6-phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, triose phosphate isomerase (Tpi1p), alcohol dehydrogenase, Ino1p, and fructose-bisphosphate aldolase (Fba1p) (Fernandez-Arenas et al., 2004). Two protective antigens were also identified, IMP dehydrogenase (Imh3p) and acetyl CoA synthetase (Acs2p) (Fernandez-Arenas et al., 2004; Pitarch et al., 2004). The agreement between the immunogenic proteins found for the murine model and for human patients reinforces the usefulness of the mouse model for studying immune response to C. albicans (Pitarch et al., 2001).

In surviving and non-surviving patients with candidiasis differing antibody profiles were found (Pitarch et al., 2004), with recovering patients maintaining relatively high levels of antibodies to the following proteins: Eno1p, Pgk1p, and Fba1p. In an attempt to identify diagnostic or prognostic biomarkers for systemic candidiasis a systematic proteomic approach has been used (Pitarch et al., 2006a). Statistical analyses demonstrated that only high levels of antibodies against 1,3-0-glucosidase (Bgl2p) and phosphoglycerate kinase (Pgk1p) were independent predictors of systemic candidiasis. High levels of anti-Bgl2 antibodies, or seropositivity for enolase antibodies, are associated with a reduced risk of death (Pitarch et al., 2006a).

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