Translational and Morphological Effects of Signalling Alcohols on C. albicans

Abstract

Candida albicans is a polymorphic yeast that can cause life threatening systemic infections in immunocompromised individuals. One key attribute of C. albicans that enhances pathogenicity is the capacity to switch morphology from vegetative to filamentous modes in response to specific environmental conditions. Stressful changes in such cellular conditions commonly cause a rapid inhibition of global protein synthesis leading to altered programmes of gene expression.Fusel alcohols induce hyphal/pseudohyphal growth, while farnesol, a quorum sensing alcohol, prevents this distinct form of growth. A variety of cell biological and genetic assays suggest that fusel alcohols and ethanol inhibit protein synthesis in C. albicans by targeting the translation initiation factor eIF2B, whereas farnesol inhibits protein synthesis in a manner that does not impact upon eIF2B activity. Rather biochemical and mass spectrometric analysis suggest farnesol affects the interaction of the mRNA with the small ribosomal subunit during translation initiation. Further analysis of the effect of farnesol on C. albicans transcript levels and ribosome association by next generation sequencing provide insight into genes that are differentially expressed following farnesol treatment. While genes involved in morphological differentiation, biofilm formation, cytokinesis and cell cycle were generally repressed, those involved in protein synthesis, oxidative stress and cellular respiration were upregulated. Intriguingly, the regulation of these functional categories of genes occurs in a co‐ordinated manner; at either the transcript level or at the level of ribosome association, but rarely at both transcriptional and post‐transcriptional levels for the same gene.