White-opaque switching in Candida albicans: cell biology, regulation, and function

SUMMARYCandida albicans remains a major fungal pathogen colonizing humans and opportunistically invading tissue when conditions are predisposing. Part of the success of C. albicans was attributed to its capacity to form hyphae that facilitate tissue invasion. However, in 1987, a second developmental program was discovered, the "white-opaque transition," a high-frequency reversible switching system that impacted most aspects of the physiology, cell architecture, virulence, and gene expression of C. albicans. For the 15 years following the discovery of white-opaque switching, its role in the biology of C. albicans remained elusive. Then in 2002, it was discovered that in order to mate, C. albicans had to switch from white to opaque, a unique step in a yeast mating program. In 2006, three laboratories simultaneously identified a putative master switch gene, which led to a major quest to elucidate the underlying mechanisms that regulate white-opaque switching. Here, the evolving discoveries related to this complicated phenotypic transition are reviewed in a quasi-chronological order not only to provide a historical perspective but also to highlight several unique characteristics of white-opaque switching, which are fascinating and may be important to the life history and virulence of this persistent pathogen. Many of these characteristics have not been fully investigated, in many cases, leaving intriguing questions unresolved. Some of these include the function of unique channeled pimples on the opaque cell wall, the capacity to form opaque cells in the absence of the master switch gene WOR1, the formation of separate "pathogenic" and "sexual" biofilms, and the possibility that a significant portion of natural strains colonizing the lower gastrointestinal tract may be in the opaque phase. This review addresses many of these characteristics with the intent of engendering interest in resolving questions that remain unanswered.