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

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 aCandida albicans MAPK homolog (Cek1p), isolated by its ability to interfere with the Saccharomyces cerevisiae MAPK mating pathway. C. albicans cells with a deletion of theCEK1 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, andSTE12 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 theC. albicans CST20, HST7, CEK1, andCPH1 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 theHST7 and CPH1 genes, disruption of theCEK1 gene adversely affects the growth of serum-induced mycelial colonies and attenuates virulence in a mouse model for systemic candidiasis.

Correlation between virulence of Candida albicans mutants in mice and Galleria mellonella larvae

“…Cpp1p, Cek1p, Hst7p and Cst20p are components of a MAP kinase pathway that plays a role in fungal virulence in mice. Cpp1 and cek1 mutants killed about 50% of infected mice after 35 days [24,25], while the wild-type C. albicans strain killed all the infected mice within 7^12 days. These mutants were also slightly less virulent in the G. mellonella model, as 20% of the larvae survived infection of either mutant after 24 h, while only 15% of the wild-type infected larvae survived.…”

“…For systemic infections, 8^10-week-old female BALB/c mice were analysed as described [24,25]. Adenylyl cyclase mutants were inoculated at higher cell densities to compensate for the slower growth [26], while standard conditions were used for the analysis of the Ras1 mutant strain [27].…”

“…In contrast, the hst7, cst20 [27] and cph1 [28] mutant strains were as virulent as the wild-type in the systemic mouse model. The cpp1, cek1 and efg1 mutants were able to kill mice in the systemic infection models, but their virulence was reduced relative to the wild-type strain [24,25,6]. These mutants also showed intermediate killing levels in the Galleria infection model, as did the strain defective in ras1 function [29].…”

Candida glabrata displays pseudohyphal growth

“…albicans is a diploid organism with no known sexual cycle. Blastoconidia of this organism readily undergo the morphological change from yeast to hyphal or pseudohyphal growth in response to a wide variety of conditions including nitrogen starvation [5]. Diploid Saccharomyces cerevisiae also switch to pseudohyphal growth when starved for nitrogen [6] and in response to a limited range of other stimuli [7].…”

Candida albicansPHO81 is required for the inhibition of hyphal development by farnesoic acid

“…Many signaling pathways and regulators involved in hyphal development have been identified as a result of strong molecular conservation among C. albicans and Saccharomyces cerevisiae in many cellular processes [6]. For example, a mitogen-activated protein kinase (MAPK) pathway involving CST20, HST7, CEK1, and CPH1, and a cAMP-dependent protein kinase A (PKA) pathway involving CAP1, TPK1, TPK2, and EFG1 promote filamentous growth [7][8][9][10][11][12]. Furthermore, the small GTP-binding protein Ras1 is required for the regulation of both MAPK and cAMP-dependent PKA pathways [13].…”