Roles of the Candida albicans Mitogen-Activated Protein Kinase Homolog, Cek1p, in Hyphal Development and Systemic Candidiasis (original) (raw)

Abstract

Extracellular signal-regulated protein kinase (ERK, or mitogen-activated protein kinase [MAPK]) regulatory cascades in fungi turn on transcription factors that control developmental processes, stress responses, and cell wall integrity. CEK1 encodes a Candida albicans MAPK homolog (Cek1p), isolated by its ability to interfere with the Saccharomyces cerevisiae MAPK mating pathway. C. albicans cells with a deletion of the CEK1 gene are defective in shifting from a unicellular budding colonial growth mode to an agar-invasive hyphal growth mode when nutrients become limiting on solid medium with mannitol as a carbon source or on glucose when nitrogen is severely limited. The same phenotype is seen in C. albicans mutants in which the homologs (CST20, HST7, and CPH1) of the S. cerevisiae STE20, STE7, and STE12 genes are disrupted. In S. cerevisiae, the products of these genes function as part of a MAPK cascade required for mating and invasiveness of haploid cells and for pseudohyphal development of diploid cells. Epistasis studies revealed that the C. albicans CST20, HST7, CEK1, and CPH1 gene products lie in an equivalent, canonical, MAPK cascade. While Cek1p acts as part of the MAPK cascade involved in starvation-specific hyphal development, it may also play independent roles in C. albicans. In contrast to disruptions of the HST7 and CPH1 genes, disruption of the CEK1 gene adversely affects the growth of serum-induced mycelial colonies and attenuates virulence in a mouse model for systemic candidiasis. Candida albicans, an opportunistic fungal pathogen, is the major causative agent of thrush and other forms of candidiasis. Diploid C. albicans alternates between a yeast form and mycelial and pseudomycelial forms but does not have a sexual cycle. Physiological temperatures, pH, and serum can promote the emergence of true hyphae from yeast cells in vitro, yet both these forms, as well as pseudohyphae, may be found in infected tissues (for a review, see reference 32). The roles of these different morphologies in pathogenesis have been controversial, but recently, hyphal differentiation has been found to be linked to systemic virulence (22, 26) and the ability of C. albicans cells to evade macrophages (26). Filamentous forms are also better than yeast forms at invading epithelial cells (7) and agar surfaces in vitro (5, 12, 34). This may be the result of both the mechanical advantages of hyphal forms in the penetration of solid substrates (11) and the production of hyphaspecific hydrolytic enzymes such as some of the secreted aspartyl proteinases which also appear to contribute to virulence (14, 40). Baker's yeast, Saccharomyces cerevisiae, is also able to switch

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