Abstract
Candida glabrata is an important human fungal pathogen known to trigger serious infections in immune-compromised individuals. Its ability to form biofilms, which exhibit high tolerance to antifungal treatments, has been considered as an important virulence factor. However, the mechanisms involving antifungal resistance in biofilms and the impact of host niche environments on these processes are still poorly defined. In this study, we performed a whole-transcriptome analysis of C. glabrata biofilm cells exposed to different environmental conditions and constraints in order to identify the molecular pathways involved in fluconazole resistance and understand how acidic pH niches, associated with the presence of acetic acid, are able to modulate these responses. We show that fluconazole treatment induces gene expression reprogramming in a carbon source and pH-dependent manner. This is particularly relevant for a set of genes involved in DNA replication, ergosterol, and ubiquinone biosynthesis. We also provide additional evidence that the loss of mitochondrial function is associated with fluconazole resistance, independently of the growth condition. Lastly, we propose that C. glabrata Mge1, a cochaperone involved in iron metabolism and protein import into the mitochondria, is a key regulator of fluconazole susceptibility during carbon and pH adaptation by reducing the metabolic flux towards toxic sterol formation. These new findings suggest that different host microenvironments influence directly the physiology of C. glabrata, with implications on how this pathogen responds to antifungal treatment. Our analyses identify several pathways that can be targeted and will potentially prove to be useful for developing new antifungals to treat biofilm-based infections.
Highlights
Candida spp. are important fungal pathogens known to trigger serious infections in immune-compromised individuals, affecting billions of people every year.[1]
In order to understand the impact of both acidic and acetateenriched environments in response to fluconazole treatment, we evaluated the whole transcriptome of C. glabrata biofilm cells by RNA sequencing
In order to thrive in these changing nutrient environments, C. glabrata has evolved sophisticated regulatory mechanisms, including major metabolic changes that have been associated with virulence and, in particular, biofilm formation.[15,16,69]
Summary
Candida spp. are important fungal pathogens known to trigger serious infections in immune-compromised individuals, affecting billions of people every year.[1]. In order to survive and successfully proliferate in the different host niches, C. glabrata must rapidly adapt to a diverse range of environmental stresses, such as temperature, pH fluctuations, and nutrient availability. Some of these niches are complex, dynamic and frequently limited in the content of carbon sources available
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