Exploring the effect of human host metabolites in Candida glabrata pathogenicity

Rosana Alves & Sandra Paiva

Candida species are leading fungal pathogens that cause both mucosal and invasive infections. These are difficult to treat since they are eukaryotes and fewer drugs are available compared to bacteria. Overuse of antifungals has resulted in the emergence of multidrug resistant species, which are even harder to eradicate. Thus, there is an urgent need to define the determinants of pathogenicity and antifungal resistance in order to improve diagnosis and develop new antifungals.

Our group at the University of Minho (Braga, Portugal) is interested in understanding the impact of host metabolites in Candida pathogenicity. In the scope of this project, we have been working in close collaboration with the groups of Professor Alistair Brown (University of Exeter, UK) and Professor Patrick Van Dijck (KU Leuven, Belgium). In our recent paper, published in npj Biofilms and Microbiomes, we show how acetate alters the transcriptional landscape of C. glabrata biofilms cells exposed to fluconazole, an antifungal drug that favors the generation of toxic sterols. The transcriptional reprogramming, observed by RNAseq experiments, in environments containing acetic acid, a ubiquitous metabolite found in the human body, confers the cells a higher ability to resist to antifungal treatments.

The gene MGE1, encoding a cochaperone involved in iron metabolism and protein import into the mitochondria, was found among upregulated genes identified in acidic conditions. We discovered that C. glabrata cells overexpressing MGE1, produce lower amounts of toxic sterols. Therefore, we proposed Mge1 as a key regulator of fluconazole susceptibility by reducing the metabolic flux towards toxic sterol formation.

Our research, and this work in particular, reveals the importance of mimicking host environments to understand how Candida species sense and respond to metabolites they encounter. By identifying and characterizing the molecular players involved in Candida adaptation to the human host, we may discover potential targets for the development of better diagnostics and new antifungal compounds to treat Candida infections.

This work was part of the Ph.D. of Rosana, who very much enjoyed her stays in the U.K. and Belgium during the course of this project.

Check out the full version of our paper:

https://www.nature.com/articles/s41522-020-0114-5

Thanks to CBMA and Rana Studio for the covering image.

Go to the profile of Sandra Cristina Almeida Paiva

Sandra Cristina Almeida Paiva

Assistant Professor, University of Minho

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