Three distinct secreted aspartyl proteinases in Candida albicans

White, Theodore C.; Miyasaki, Shelley H.; Agabian, Nina

doi:10.1128/jb.175.19.6126-6133.1993

Cited by 156 publications

(176 citation statements)

References 19 publications

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“…SAP1 and SAP3 were not activated to high levels in any of the infection models used; nevertheless, significant expression of these genes was detected in some animals. Interestingly, SAP1 and SAP3 are phase-specific genes in the C. albicans strain WO-1, where they are expressed only in the opaque phase but not in the white phase (29). Although strain SC5314, from which our reporter strains are derived, does not display the whiteopaque switching, a similar phenomenon may result in a phasevariable expression of the SAP1 and SAP3 genes in this strain.…”

Section: Discussionmentioning

confidence: 96%

Differential activation of a Candida albicans virulence gene family during infection

Staib¹,

Kretschmar²,

Nichterlein³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

147

138

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The yeast Candida albicans is a harmless commensal in most healthy people, but it causes superficial as well as life-threatening systemic infections in immunocompromised patients. C. albicans can colonize or infect virtually all body sites because of its high adaptability to different host niches, which involves the activation of appropriate sets of genes in response to complex environmental signals. We have used an in vivo expression technology that is based on genetic recombination as a reporter of gene expression to monitor the differential activation of individual members of a gene family encoding secreted aspartic proteinases (Saps), which have been implicated in C. albicans virulence, at various stages of the infection process. Our results demonstrate that SAP expression depends on the type of infection, with different SAP isogenes being activated during systemic disease as compared with mucosal infection. In addition, the activation of individual SAP genes depends on the progress of the infection, some members of the gene family being induced immediately after contact with the host, whereas others are expressed only after dissemination into deep organs. In the latter case, the number of invading organisms determines whether induction of a virulence gene is necessary for successful infection. The in vivo expression technology allows the elucidation of gene expression patterns at different stages of the fungus-host interaction, thereby revealing regulatory adaptation mechanisms that make C. albicans the most successful fungal pathogen of humans and, at the same time, identifying the stage of an infection at which certain virulence genes may play a role.

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Section: Discussionmentioning

confidence: 96%

Differential activation of a Candida albicans virulence gene family during infection

Staib¹,

Kretschmar²,

Nichterlein³

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

147

138

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“…All together, these studies indicate that phenotypic switching indeed occurs at the sites of infection and, possibly, that different switch phenotypes predominate in different anatomical locations of the host. With the demonstration that the expression of specific virulence and pathogenesis traits are correlated with switch phenotype (18,28,30,31), the importance of this phenomenon to the natural history of C. albicans disease in humans appears significant.…”

mentioning

confidence: 99%

Metabolic specialization associated with phenotypic switching inCandidaalbicans

Lan

Newport

Murillo

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

266

277

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Phase and antigenic variation are mechanisms used by microbial pathogens to stochastically change their cell surface composition. A related property, referred to as phenotypic switching, has been described for some pathogenic fungi. This phenomenon is best studied in Candida albicans, where switch phenotypes vary in morphology, physiology, and pathogenicity in experimental models. In this study, we report an application of a custom Affymetrix GeneChip representative of the entire C. albicans genome and assay the global expression profiles of white and opaque switch phenotypes of the WO-1 strain. Of 13,025 probe sets examined, 373 ORFs demonstrated a greater than twofold difference in expression level between switch phenotypes. Among these, 221 were expressed at a level higher in opaque cells than in white cells; conversely, 152 were more highly expressed in white cells. Affected genes represent functions as diverse as metabolism, adhesion, cell surface composition, stress response, signaling, mating type, and virulence. Approximately one-third of the differences between cell types are related to metabolic pathways, opaque cells expressing a transcriptional profile consistent with oxidative metabolism and white cells expressing a fermentative one. This bias was obtained regardless of carbon source, suggesting a connection between phenotypic switching and metabolic flexibility, where metabolic specialization of switch phenotypes enhances selection in relation to the nutrients available at different anatomical sites. These results extend our understanding of strategies used in microbial phase variation and pathogenesis and further characterize the unanticipated diversity of genes expressed in phenotypic switching.M any pathogenic bacteria, fungi, and protozoa have evolved strategies for alternative expression of surface-related phenotypes, a facility that enables their escape from immune surveillance and adaptation to changing environments. Antigenic variation, as displayed by African trypanosomes, Neisseria spp. and Borrelia spp., is a well studied example (1-4). Variation between phenotypes can be reversible and stochastic, leading to the expression of predefined traits which, when superimposed on classical environmentally responsive sensor mechanisms, extend the phenotypic diversity of the pathogen. In bacteria, many mechanisms have been described that lead to the expression of contingency loci that regulate expression of pili, flagella, adhesins, and surface-associated lipopolysaccharides and lipoproteins (5, 6).Strains of Candida albicans, the most important fungal pathogen of humans, are able to spontaneously and reversibly switch phenotypes at high frequency (7). Three different switching systems were first described by . C. albicans strain 3153A alternates between phenotypes distinguished by at least seven colony morphologies; conversion from the original smooth to other variant colony morphologies occurs at a combined frequency of 1.4 ϫ 10 Ϫ4 (11). Another system includes strains that switch between coloni...

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“…Regulation of SAPS by phenotypic switching (White et al, 1993; and serum/hypha formation are particularly relevant to pathogenesis. Induction of SAP may involve a signal transduction event initiated by contact sensing of extracellular protein, with specific sequence requirements (Lerner & Goldman, 1993).…”

mentioning

confidence: 99%

Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: Implications for the design of antifungal agents

et al. 1996

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The three-dimensional structure of a secreted aspartic protease from Candida albicans complexed with a potent inhibitor reveals variations on the classical aspartic protease theme that dramatically alter the specificity of this class of enzymes. The structure presents: (1) an 8-residue insertion near the first disulfide (Cys 45-Cys 50, pepsin numbering) that results in a broad flap extending toward the active site; (2) a 7-residue deletion replacing helix h,, (Ser 110-Tyr 114), which enlarges the S, pocket; (3) a short polar connection between the two rigid body domains that alters their relative orientation and provides certain specificity; and (4) an ordered 11-residue addition at the carboxy terminus. The inhibitor binds in an extended conformation and presents a branched structure at the P3 position. The implications of these findings for the design of potent antifungal agents are discussed.

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Three distinct secreted aspartyl proteinases in Candida albicans

Cited by 156 publications

References 19 publications

Differential activation of a Candida albicans virulence gene family during infection

Differential activation of a Candida albicans virulence gene family during infection

Metabolic specialization associated with phenotypic switching inCandidaalbicans

Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: Implications for the design of antifungal agents

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