Genome-wide translational response of Candida albicans to fluconazole treatment

Abstract

ABSTRACT Azoles are commonly used for the treatment of fungal infections, and the ability of human fungal pathogens to rapidly respond to azole treatment is critical for the development of antifungal resistance. While the roles of genetic mutations, chromosomal rearrangements, and transcriptional mechanisms in azole resistance have been well-characterized, very little is known about post-transcriptional and translational mechanisms that drive this process. In addition, most previous genome-wide studies have focused on transcriptional responses to azole treatment and likely serve as inaccurate proxies for changes in protein expression due to extensive post-transcriptional and translational regulation. In this study, we use ribosome profiling to provide the first picture of the global translational response of a major human fungal pathogen, Candida albicans, to treatment with fluconazole (Flu), one of the most widely used azole drugs. We identify sets of genes showing significantly altered translational efficiency, including genes associated with a variety of biological processes such as the cell cycle, DNA repair, cell wall/cell membrane biosynthesis, transport, signaling, DNA- and RNA-binding activities, and protein synthesis. We observe both similarities and differences among the most highly represented gene categories (as defined by gene ontology) that are regulated by fluconazole at the translational vs transcriptional levels. Importantly, however, very few genes that are translationally regulated by fluconazole are also controlled transcriptionally under this condition. Our findings suggest that C. albicans possesses distinct translational mechanisms that are important for the response to antifungal treatment, which could eventually be targeted by novel antifungal therapies. IMPORTANCE Azoles are one of the most commonly used drug classes to treat human fungal pathogens. While point mutations, chromosomal rearrangements, and transcriptional mechanisms that drive azole resistance have been well-characterized, we know very little about the role of translational mechanisms. In this study, we determined the global translational profile of genes that are expressed in the major human fungal pathogen Candida albicans in response to fluconazole, one of the most widely used azole drugs. We find both similarities and differences among the most highly represented categories of genes regulated by fluconazole at the transcriptional and translational levels. Interestingly, however, many of the specific genes that are regulated by fluconazole at the translational level do not appear to be controlled by transcriptional mechanisms under this condition. Our results suggest that distinct C. albicans translational mechanisms control the response to antifungals and could eventually be targeted in the development of new therapies.

Keywords

• fluconazole
• ribosome profiling
• translational control
• transcriptional profiling
• Candida albicans