Gene regulation during high-frequency switching in Candida albicans.

In 1984, it was discovered that cells of a common laboratory strain of Candida albicans could be induced to switch frequently and reversibly between a number of distinct colony phenotypes by exposing them, for a brief period, to a low dose of UV irradiation (Slutsky et al., 1985). It was subsequently demonstrated that most strains of C. albicans were capable of high-frequency phenotypic switching, and that many commensal and infecting strains were already in a high-frequency mode of switching (PomCs et al., 1985; Odds & MersonDavies, 1989; Soll et al., 1987, 1989; Hellstein et al., 1993). Evidence has also emerged that pathogenic strains, on average, switch at higher frequencies than commensal strains (Hellstein et al., 1993 ; Gallagher et al., 1992; Soll, 1992; Jones et al., 1994), and that different strains form somewhat different colony morphologies in their switching repertoires, but follow the same rules (Soll, 1992). Switching was initially discriminated through differences in colony morphology on zinc-limiting agar (Slutsky et al., 1985; Soll, 1992), and in most strains, differences in colony morphology have been demonstrated to be due to differences in the spatial distribution of budding cells, pseudohyphae and hyphae in the colony dome (Soll et al., 1991). However, with the discovery (Slutsky et al., 1987) and characterization (Slutsky et al., 1987; Anderson & Soll, 1987; Anderson et al., 1989, 1990; Ghannoum et al., 1990; Kennedy et al., 1988; Kolotila & Diamond, 1990; Rikkerink et al., 1988; Vargas et d., 1994) of the white-opaque transition in C . albicans strain WO-1, it became clear that switching could affect simultaneously an extraordinary variety of cellular characteristics, which is not the case for other bacterial and eukaryotic switching systems (Glasgow et al., 1989; Swanson & Koomey, 1989; Barbour, 1989; Donelson, 1989). It also became clear that switching was distinct from the bud-hypha transition, although, as will be described, the two developmental programmes manipulate the transcription of at least one common gene by overlapping regulatory circuitry (Srikantha & Soll, 1993). After the discovery of switching in strain 315312, a literature search uncovered earlier studies on the variability of colony morphology in C . albicans that are now rarely cited, but that very likely involved analyses of switch phenotypes (Mackinnon, 1940; Negroni, 1935 ; Brown-Thomsen, 1968 ; Vogel & Sponeler, 1970). At the time switching was demonstrated in C. albicans strain 3153A, Porn& et al. (1985) demonstrated switching between a smooth and rough phenotype in C. albicans strain 1001, and suggested that switching was due to mitotic recombination, although this seemed improbable since the same authors presented evidence for highfrequency reversibility. It is now known that highfrequency phenotypic switching is quite pleiotropic, but phenotypically precise, and that it can affect a number of putative virulence traits (Soll, 1992), reinforcing the original suggestion that it represents, in its own right, a pathogenic strategy for generating phenotypic variability to deal with the broad variety of environmental changes a strain faces as a commensal and pathogen.