Metabolic specialization associated with phenotypic switching inCandidaalbicans

Abstract

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...

Stress-Induced Phenotypic Switching inCandida albicans

“…Switching between states occurs infrequently, with an average of one event every 10,000 cell divisions (Rikkerink et al, 1988). More than 450 genes are differentially regulated between the white and the opaque states (Lan et al, 2002;Tsong et al, 2003), and these differences affect C. albicans pathogenicity, mating efficiency, and biofilm formation . Thus, white cells are more virulent in a mouse tail-vein model of systemic infection, while opaque cells are more efficient at colonization of the skin in a cutaneous model of infection (Kvaal et al, 1997(Kvaal et al, , 1999.…”

“…Opaque cells are also the mating competent form of C. albicans, because they have been shown to undergo mating at least a million times more efficiently than white cells . Increased mating efficiency is due, at least in part, to increased expression of genes involved in mating signaling (Lan et al, 2002). White and opaque cells have also been shown to differ in their interaction with immune cells.…”

Nuclear fusion occurs during mating in Candida albicans and is dependent on the KAR3 gene

“…Transcriptional profiling of white-phase and opaque-phase cells has shown that these phases differentially regulate around 400 genes (Lan et al ., 2002;Tsong et al ., 2003). Several genes implicated in mating are upregulated in the opaque phase, suggesting that opaques are primed to mate.…”

“…Several genes implicated in mating are upregulated in the opaque phase, suggesting that opaques are primed to mate. However, approximately one-third of the genes regulated by the white-opaque switch are implicated in metabolism, suggesting that a major role of the white-opaque transition may be to allow C. albicans to adapt to different microenvironments in the host (Lan et al ., 2002). It is possible that the white to opaque transition directs mating to a particular host niche.…”

Crystal structure of the WOPR-DNA complex and implications for Wor1 function in white-opaque switching of Candida albicans

“…Important to its pathogenesis and commensalism is its ability to switch between different morphological forms [2][3][4]. C. albicans can switch between two distinct cell types, white and opaque, which have different properties including cell shape, colonial morphology, metabolic preference, mating ability, gene expression pattern, and host tissue preference [5][6][7][8][9]. White-opaque switching is controlled through expression of a master regulator, Wor1 (whiteopaque switching regulator 1), which is highly upregulated in opaque cells and is required for both the transition to and maintenance of the opaque cell type [10][11][12][13].…”